Method for separating and detecting an analyte

ABSTRACT

A method for separating and analyzing an analyte is provided which comprises, in a first position, transferring a liquid sample to a multiwell plate with a pipette tip, replacing the tips in the tip rack in the same position, and re-using the pipette tips for aspirating and dispensing liquid.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application claims the benefit of priority under 35 U.S.C.§119 of EP09178713.5, filed Dec. 10, 2009, the entire contents of whichare hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to an automated analytical system and anautomated method for separating and detecting an analyte, as well as anautomated analytical instrument.

BACKGROUND OF THE INVENTION

Analytical systems used in the field of diagnostics require processingof samples comprising analytes to be analyzed.

Such processing involves transfer of vessels, or of liquid samples andreagents from one vessel to another. For higher throughput, simultaneousprocessing is often performed using multiple consumables, such aspipette tips and multiwell plates. Especially with systems for nucleicacid analysis, re-use of pipette tips may be limited due tocontamination.

SUMMARY OF THE INVENTION

The present invention relates to an analytical apparatus. The terms“analytical apparatus” (400) and “analyzer” (400) and “analyticalinstrument” (400) are used interchangeably. An analytical systemcomprises an analyzer. An analyzer comprises one or more modules orcells. Said modules or cells comprise stations for carrying out theprocessing and/or analysis of an analyte.

The invention also relates to a method for isolating and analyzing ananalyte that may be present in a fluid sample. Preferably, said methodcomprises the automated steps of:

-   -   a) transferring said fluid sample from a sample vessel to a        processing vessel with a pipette tip;    -   b) combining together a solid support material and said fluid        sample in a well of said processing vessel for a period of time        and under conditions sufficient to permit said analyte to be        immobilized on the solid support material;    -   c) isolating the solid support material from other material        present in the fluid sample in a separation station; and    -   d) purifying the analyte in the separation station by separating        the fluid sample from the solid support material and washing the        materials one or more times with a wash buffer.

Furthermore, the present invention relates to consumables which areoptimized for use in automated analytical systems.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a view of an assembled rack loaded with pipette tips.

FIG. 2 shows a view of a rack without loaded tips.

FIG. 3 shows a cross section through the longer side walls of the rackloaded with two types of pipette tips.

FIG. 4 shows a perspective view of the top-side of the lower rack.

FIG. 5 shows a perspective view of the bottom part of the lower rack.

FIG. 6 shows a perspective view of the top-side of the insert rack.

FIG. 7 shows a perspective view of the bottom part of the insert rack.

FIG. 8 shows a perspective view of the top-side of the upper rack.

FIG. 9 shows a perspective view of the bottom part of the upper rack.

FIG. 10 shows a partial cross-sectional view through the assembled rackwith pipette tips loaded.

FIG. 11 shows a partial cross-sectional view through the assembled rackwithout pipette tips loaded.

FIG. 12 shows a perspective view of the upper rack loaded with pipettetips, with details of the first type of tips sitting on the throughbore-holes.

FIG. 13 shows a perspective view of the upper rack loaded with pipettetips, with details of the second type of tips sitting on the rim ofthrough bore-holes.

FIG. 14 (a) shows a perspective view of the first and second types ofpipette tips; (b) shows a pipette needle.

FIG. 15 shows a detailed perspective view of the alignment of thepositioning elements on the bottom of the process head and thepositioning elements on the top of the upper rack for alignment of theprocess head with the first type of pipette tips.

FIG. 16 shows a detailed perspective view of the engagement of thepositioning elements on the bottom of the process head and thepositioning elements on the top of the upper rack.

FIG. 17 shows a detailed perspective view of the alignment of thepositioning elements on the bottom of the process head and thepositioning elements on the top of the upper rack for alignment of theprocess head with the second type of pipette tips.

FIG. 18 shows a detailed perspective view of the process head followingengagement of the second type of pipette tips.

FIG. 19 shows a perspective view of the positioning elements on a sidewall of the rack and on the process deck for initial positioning of therack within the analyzer.

FIG. 20 shows a perspective view of the engagement of positioningelements on a side wall of the rack and on the process deck for initialpositioning of the rack within the analyzer.

FIG. 21 shows a detailed sectional view of the bottom of a chamber foraccommodating the second type of pipette tips in the insert rack and theridge between two chambers of the lower rack.

FIG. 22 shows a detailed sectional view of the bottom of chambers of thelower rack.

FIG. 23 shows a sectional view of the site of interaction between theupper rack and the insert rack with a second type of pipette tipinserted into a through bore-hole.

FIG. 24 shows a sectional view of the site of interaction between theupper rack and the insert rack without a second type of pipette tipinserted into a through bore-hole.

FIG. 25 Partial view of a second embodiment of tip rack.

FIG. 26 shows a perspective view of the Processing Plate.

FIG. 27 shows a perspective view of the Processing Plate from theopposite angle.

FIG. 28 shows a top view of the processing plate.

FIG. 29 shows a cross-sectional view along the longer side of theprocessing plate.

FIG. 30 shows a partial view of the cross-sectional view.

FIG. 31 shows a perspective view of the longer side of the Processingplate.

FIG. 32 shows a perspective view of the bottom of the Processing plate.

FIG. 33 shows a more vertical perspective view of the bottom of theProcessing plate.

FIG. 34 shows the fitting of the smaller magnets of the first preferredembodiment of the separation station with the vessels of the Processingplate.

FIG. 35 shows a horizontal cross sectional view of the central region ofthe Processing plate and vessels.

FIG. 36 shows the fitting of the Processing plate in a station forreceiving the Processing plate (e.g. the magnetic separation station),with the locking mechanism disengaged.

FIG. 37 shows the fitting of the Processing plate in a station forreceiving the Processing plate (e.g. the magnetic separation station),with the locking mechanism engaged.

FIG. 38 shows schematic drawings of an analyzer comprising differentstations, modules or cells.

FIGS. 39 (a) to (d) show different views of the second embodiment of themagnetic separation station.

FIGS. 40 (a) to (c) show a view of the first embodiment of the magneticseparation station holding the Processing plate, with the first type ofmagnets in the uppermost Z-position, and the second type of magnets inthe lowermost Z-position.

FIGS. 41 (a) to (c) show a view of the first embodiment of the magneticseparation station holding the Processing plate, with the first type ofmagnets in the uppermost Z-position, and the second type of magnets inthe uppermost Z-position.

FIGS. 42 (a) to (c) show a view of the first embodiment of the magneticseparation station holding the Processing plate, with the first type ofmagnets in the lowermost Z-position, and the second type of magnets inthe uppermost Z-position.

FIGS. 43 (a) to (c) show a view of the first embodiment of the magneticseparation station holding the Processing plate, with the first type ofmagnets in the lowermost Z-position, and the second type of magnets inthe lowermost Z-position.

FIGS. 44 (a) to (d) shows the AD plate and frame with sealing foil instorage position (a), with lifted lid (b), during rotation of lid (c)and in sealing position (d).

FIG. 45 (a) shows a sectional side view of the AD plate and frame insealing position; (b) shows a sealing foil with two layers and the topof the lid comprising a frame.

FIGS. 46 (a) and (b) show side and top sectional views of one corner ofthe AD plate and frame in storage position.

FIGS. 46 (c) and (d) show side and top sectional views of a corner ofthe AD plate and frame in sealing position.

FIGS. 47 (a) and (b) show the fitting of the AD plate in a station forreceiving the AD plate with the locking mechanism disengaged (a) orengaged (b).

FIG. 48 shows the interaction of a tip rack with the gripper fingers.The form-lock of the gripping prevents movement in X and Y direction(see right hand panel).

FIG. 49 shows the interaction between the handler and a multiwell plate.The gripper fingers interlock with openings on the multiwell plate,resulting in a form-lock gripping.

FIGS. 50 (a) and (b) show the handler connected to a robotic arm, andthe attachment and release of the consumable by the gripper fingers; (c)shows that the handler interacts with different consumable with the sameinterface.

FIG. 51 is a schematic drawing of an analyzer embodiment with stackerswhich specifically recognize certain consumables.

FIG. 52 shows a schematic drawing of hardware architecture with theworkflows from consumable holders to different modules, and betweendifferent modules (shown by arrows); and from different modules back tothe waste holder.

FIG. 53 shows a schematic view of systems with modules with predefinedworkflow timing and a transport module which is either linear (a) orcircular (b); (c) shows a preferred system with one module of a firsttype, two modules of a second type and four modules of a third type.

FIG. 54 shows a schematic front view of an analytical apparatusaccording to the invention.

FIG. 55 shows a top view (a) and a side view (b) of the air-lock.

FIG. 56 shows a perspective view of an analytical apparatus of thepresent invention with front walls.

DETAILED DESCRIPTION OF THE INVENTION Analytical Apparatus and Methodfor Isolating and Analyzing an Analyte

A method for isolating and analyzing an analyte that may be present in afluid sample is disclosed. Said method comprises the automated steps of:

-   -   a) transferring said fluid sample from a sample vessel to a        processing vessel with a pipette tip;    -   b) combining together a solid support material and said fluid        sample in a well of said processing vessel for a period of time        and under conditions sufficient to permit said analyte to be        immobilized on the solid support material;    -   c) isolating the solid support material from other material        present in the fluid sample in a separation station; and    -   d) purifying the analyte in the separation station by separating        the fluid sample from the solid support material and washing the        materials one or more times with a wash buffer.

Preferably, said pipette tip used in step (a) is re-used after step (a).

In a preferred embodiment, said pipette tip is a pipette tip of a firsttype, and said pipette tip of a first type is stored in a rackcomprising pipette tips of a first type and pipette tips of a secondtype. Preferably, said pipette tips of a first and second type arestored in said rack at least between being used for pipetting.

In a preferred embodiment of the method hereinbefore described, step a)comprises:

-   -   a1) engaging pipette tips of a first type which are held in a        rack in a first position with a first process head;    -   a2) transferring said fluid sample from a sample vessel to a        processing vessel with pipette tips of a first type engaged to a        first process head;    -   a3) placing said pipette tips in said rack and disengaging said        pipette tips from said process head;    -   a4) transporting said rack comprising said pipette tips and said        processing vessel to second positions;    -   a5) engaging said pipette tips of a first type which are held in        said rack with a second process head in said second position.

Preferably, the processing vessel comprises more than one receptacle.More preferably, the processing vessel is a multiwell plate. The methodpreferably additionally comprises the step of:

-   -   e) reacting said purified analyte with reagents necessary to        obtain a detectable signal.

Re-use of pipette tips leads to a reduction of disposable consumablesused in the analytical method and to cost reductions. In a preferredembodiment, the washing in step d) comprises aspirating and dispensingthe washing buffer with a process head engaged to pipette tips.

The term “receptacle” as used herein relates to a single vessel (ortube) or to a tube comprised in a multi-tube unit, or to a well (orvessel) of a multiwell plate.

The term “vessel” is understood to mean a single vessel or a singlevessel in a multi-tube unit, a multiwell plate or a multi-tube unit or awell of a multiwell plate.

In a preferred embodiment, the reacting comprises generating adetectable signal. More preferably, the method additionally comprisesthe step of detecting a detectable signal.

The term “analyte” as used herein may be any type of biomolecule whichis of interest for detection, and the detection thereof is indicative ofa diagnostic status of an organism. The organism can be animal or, morepreferably, human. Preferred analytes are proteins, polypeptides,antibodies or nucleic acids. More preferably, the analyte is a nucleicacid.

The term “reacting” as used herein relates to any type of chemicalreaction of the analyte with reagents that is necessary to obtain adetectable signal. Preferably, said reacting comprises amplification.Amplification may be understood as any type of enhancement of a signal.Thus, amplification can be a conversion of a molecule by an enzyme,wherein said enzyme is coupled or bound to the analyte, leading to adetectable signal, wherein more signal molecules are formed than analytemolecules are present. One such non-limiting example is a formation of achemiluminescent dye, e.g. using ECL. The term amplification furtherrelates to nucleic acid amplification, if the analyte is a nucleic acid.This includes both linear, isothermal and exponential amplifications.Non-limiting examples of nucleic acid amplification methods are TMA,SDA, NASBA, PCR, including real-time PCR. Such methods are well known tothe skilled person.

The term “solid support” as used herein relates to any type of solidsupport to which the analyte is capable of binding, either directly byadsorption, or indirectly and specifically. Indirect binding may bebinding of an analyte to an antibody immobilized on the solid support,or binding of a tag to a tag binding compound, e.g. binding of 6×Histags to Ni-chelate. When the analyte is a nucleic acid, such indirectbinding is preferably by binding to a capture nucleic acid probe whichis homologuous to a target sequence of the nucleic acid of interest.Thus, using capture probes attached on a solid support, a targetanalyte, preferably a target nucleic acid, can be separated fromnon-target material, preferably non-target nucleic acid. Such captureprobe is immobilized on the solid support. Solid support material may bea polymer, or a composition of polymers. Other types of solid supportmaterial include magnetic silica particles, metal particles etc.

Preferred direct binding of nucleic acid to silica particles occurs inthe presence of chaotropic compounds. Such binding may also be referredto as direct binding, as opposed to the indirect binding describedabove. Preferably, the solid supports are silica particles whichcomprise a magnetic or magnetizable material.

A “separation station” is understood to be a station where an analyte isseparated from a solid support.

In a preferred embodiment of the method hereinbefore described, thetransporting of said rack comprising said pipette tips and saidprocessing vessel to a second positions occurs between a separate firstcell of an analytical instrument and a separate second cell, preferablya processing cell, of said analytical system. Preferably, the rackcomprises independent chambers to accommodate pipette tips.

In a preferred embodiment, the first type of pipette tips is re-used forthe washing in step d).

In a preferred embodiment, the rack additionally comprises a second typeof pipette tips. Further preferred is a method as hereinbeforedescribed, wherein between step d) and e), the analyte is eluted fromthe magnetic particles. A preferred embodiment comprises the transfer ofthe analyte from said processing vessel, which is preferably a multiwellplate, to a reaction vessel, which is preferably a multiwell plate, withsaid second type of pipette tips.

An analytical system for isolating an analyte is disclosed, said systemcomprising:

-   -   a) a first position comprising a first receptacle holding a        liquid sample comprising an analyte, a second receptacle for        holding a liquid sample, a rack holding pipette tips, and a        first process head for transferring a liquid sample from the        first receptacle to a second receptacle,    -   b) a second position comprising a station for receiving said        second receptacle, and a rack holding station for receiving said        rack,    -   c) a transfer system for transferring the second receptacle and        the rack holding pipette tips between the first position and the        second position.

Preferably, the positions are separate cells. The rack transferred bysaid transfer system preferably comprises pipette tips which were usedin the first position. In a preferred embodiment, the first receptacleis a sample vessel and the second receptacle is a processing vessel.Further preferred is a processing vessel which is a multiwell vessel.Preferred embodiments of said stations are described hereinafter.

In the analytical system herein described, the transport systempreferably transfers the receptacle and the rack from the first positionto the second separate position. Preferably, the second separateposition comprises a magnetic separation station. The analytical systemadditionally preferably comprises an amplification station.

The transport system of the preferred system comprises a handlerconstructed and arranged to grip and transport said rack and saidprocessing vessel from a first to a second location within the system.Further preferred handlers are disclosed herein.

The system is preferably fully automated.

An automated analyzer for isolating and analyzing an analyte comprisinga plurality of stations disposed within said analyzer is also disclosed.The plurality of stations comprises a sample dispensing station disposedin a first location. Preferably, said sample dispensing station isconstructed and arranged to dispense liquid sample comprising an analytefrom a sample vessel to a processing vessel with pipette tips held in arack. Further preferred sample dispensing stations are stationscomprising a sample vessel, a processing vessel and a liquid dispensingunit. Said liquid dispensing unit is preferably a process device.

The automated analyzer further comprises a separation station disposedin a second location. Preferably, said separation station is constructedand arranged to receive said processing vessel holding said liquidsample and said rack holding pipette tips used in the sample dispensingstation and to separate an analyte from other material present in theliquid sample. Another preferred embodiment of a separation station is aseparation station comprising movable magnets.

The automated analyzer further comprises a reaction station disposed ina third location, wherein said reaction station is constructed andarranged to analyze said analyte to obtain a detectable signal. Anotherpreferred embodiment of a reaction station is a station comprising anincubator. Preferably, said incubator is a temperature-controlledincubator. More preferably, said incubator is held at one constanttemperature. Another preferred embodiment of an incubator is athermocycler block. Preferably, a detector for detecting the detectablesignal is integrally connected to the reaction station, more preferablyto the incubator as hereinbefore described. A preferred detectorcomprises a nucleic acid quantification system for periodic measurementand quantification. More preferably, the detector additionally comprisesa nucleic acid detection system which detects the signal and ascertainsthe presence or absence of the nucleic acid in the reaction receptaclebased upon whether or not a signal above a threshold level is detected.

Alternatively, the automated analyzer additionally comprises a detectingstation. The automated analyzer further comprises a transport mechanism.Said transport mechanism comprises a handler for handling consumables.Said handler preferably transports a consumable between stations. In oneembodiment, said transport mechanism is constructed and arranged totransport said sample vessel and said rack from said sample dispensingstation to said separation station. Further preferred embodiments of theautomated analyzer herein described are individual or combined featuresdisclosed herein.

In a preferred embodiment, the analytical apparatus (400) comprises atleast one module (401) for processing an analyte, said processingcomprising pipetting of a liquid. The processing module (401) comprises:

-   -   a) a process head (35) for engaging with pipette tips (3, 4),        said process head (35) comprising positioning elements (36)        arranged in the lower surface (61) of said process head (35),    -   b) a tip rack (60, 70) holding pipette tips (3, 4), wherein said        tip rack (60, 70) comprises positioning elements (31, 32, 33,        34) capable of engaging mechanically with the positioning        elements (36) on the process head (35).

In a preferred embodiment of the analytical apparatus (400) hereinbeforedescribed, said processing module (401) is a module for isolation andpurification of an analyte. Therefore, the term “processing” as usedherein is understood to relate to isolation and/or separation and/orcapture and/or purification of an analyte. Preferably, said apparatus(400) comprises a module for preparing samples for processing (402).Preferably, said apparatus (400) comprises a module for amplification ofsaid analyte (403). In one preferred embodiment, said apparatusadditionally comprises a module (404) for transferring amplificationreagents from a storage receptacle to a receptacle comprising a purifiedanalyte. Further preferred embodiments of said apparatus are ashereinbefore and hereinafter described.

An automated analyzer (400) for use in performing a nucleic acid basedamplification reaction is also disclosed. Said analyzer comprises aplurality of modules (401, 402, 403). One module is a processing moduledisposed at a first location within the analyzer constructed andarranged to separate a nucleic acid from other material in a sample.Said processing module comprises a separation device as hereindescribed. The analyzer further comprises an amplification moduledisposed and arranged at a second location within the analyzer. Theamplification module comprises a temperature-controlled incubator forincubating the contents of at least one receptacle, preferably of amultiwell plate comprising the separated nucleic acid and one or moreamplification reagents for producing an amplification product indicativeof the target nucleic acid in the sample.

An analytical system comprising a holding station and a multiwell plateset as described herein is a further preferred embodiment of theanalytical system disclosed herein. Preferably, said multiwell plate setis fixed in said holding station. Preferably, the multiwell platecomprises a base with a rim which comprises recesses, wherein apositioning and fixing element, preferably a latch-clip (FIGS. 47 (a)and (b)), on said holding station contacts said recesses, wherein saidcontact exerts a downwards pressure on the base of the multiwell plate,thereby fixing the multiwell plate in the holding station. Furtherpreferred embodiments of the analytical system comprise individual orcombined features described herein.

Furthermore, an analytical instrument is disclosed comprising:

a processing module for isolating and purifying an analyte comprising aholding station (470) for holding a rack comprising pipette tips, saidrack comprising at least one recess located on one side wall of therack, and at least one recess located on an opposite second side wall ofsaid rack, wherein said holding station comprises a fixing element,preferably a latch-clip and wherein said fixing element, preferably alatch-clip interacts with said recess by exerting a force against thebottom of said recess; and

a module (403) for analyzing said purified analyte by reacting saidanalyte with reagents necessary to obtain a detectable signal.

The analytical instrument preferably additionally comprises a liquidhandling module (404, 500). Further embodiments and preferredembodiments of the analytical instrument are described herein, eitherseparately or as combinations of embodiments. Preferred embodiments ofanalyzers are shown in FIGS. 38 and 51.

The analytical instrument disclosed herein preferably additionallycomprises a sealing station (410). The sealing station (410) ispreferably located in the process module (401).

The term “module” and “cell” are used interchangeably herein.

Tip Rack

A tip rack is disclosed. Such tip racks comprise pipette tips. Tip racksare commonly used in analytical systems for providing pipette tips forpipetting liquids to the system. Such tips are disposable, but can bere-used at least once. Said tip rack comprises independent chambers foraccommodating pipette tips.

A preferred rack is disclosed for holding pipette tips. Said rackcomprises independent chambers for accommodating at least a first typeof pipette tips and a second type of pipette tips. In one embodiment,said rack comprises more than one part. In another embodiment, said rackis an integral one part rack. Preferably, the volume of the first typeof pipette tips is at least 1 ml and the volume of the second type ofpipette tips is below 1 ml. More preferably, the volume of the firsttype of pipette tips is between 1 ml and 1.5 ml, and the volume of thesecond type of pipette tip is between 10 ul and 600 ul.

Preferably, the first type of pipette tips and the second type ofpipette tips are stored in said rack in alternate rows. In oneembodiment, the rack comprises 48 pipette tips of a first type and 48pipette tips of a second type. Other numbers of tips are, however, alsoencompassed. The rack may also comprise more pipette tips of one typethan of the other type.

In one embodiment, the independent chambers are vessels.

A three part rack is disclosed for holding pipette tips. Said rackcomprises features which make it particularly suited for automatedsystems. Said rack comprises three parts. An upper rack comprises asurface plate, said surface plate comprises through bore-holes with aseating area for inserting pipette tips in said rack. The rack alsocomprises a lower rack. Said lower rack comprises independent chambersfor accommodating pipette tips of a first type. The third part of saidrack is an insert rack. The insert rack is inserted into said lowerrack. The insert rack comprises chambers for accommodating pipette tipsof a second type. The upper rack is assembled on top of said lower rackand said insert rack.

The rack is, thus, suited for holding more than one type of pipettetips. This is useful in systems in which different volumes of liquid arepipetted with pipette tips.

The rack disclosed herein comprises contamination protection forprotecting individual tips from contaminating each other. Suchcontamination may occur due to droplets or aerosols. Such protection isof particular importance if pipette tips are place in the rack after afirst use, before being re-used again. Thus, the rack preferablycomprises rows of open chambers for holding a second type of pipettetips. More preferably, said open chambers have a bottom. This bottomseparates the chamber holding the second type of pipette tips from thechambers holding the first type of pipette tips. This reduces the riskof contaminations between the first and second types of tips.

In a preferred embodiment, said rows of open chambers for holdingpipette tips of a second type alternate with rows of independentchambers for accommodating said pipette tips of a first type.Preferably, the inner area of the independent chambers in the lower rackfor accommodating said pipette tips of a first type is larger than theinner area of the through bore holes for inserting pipette tips.

In a preferred embodiment, a wall located on the inside of the sidewalls of the independent chambers of the lower rack for holding pipettetips of a first type extend from the bottom of the lower rack to belowthe top of the side wall of the independent chambers of the lower rack.Preferred embodiments described hereinbefore and hereinafter relate to arack comprising pipette tips of a first type, more preferablyadditionally comprising a second type of pipette tips.

Further preferred embodiments of any one tip rack disclosed hereincomprise features described above and below without limitation to onespecific embodiment by combination with any one of the embodimentsdisclosed herein.

A first embodiment of an exemplary rack (60) (FIGS. 1 and 2) comprisesmultiple parts. An upper rack (1), a lower rack (2) and an insert rack(14) are assembled to one rack for holding and re-using tips (4). In apreferred embodiment, a first type of tips (4) and a second type of tips(3) are held in said rack (60). In a more preferred embodiment, tips (4)for sampling, isolating and purifying an analyte and tips (3) fortransferring the eluted analyte are held in one rack according to theinvention. Most preferably, the rack (60) elongated tips with a largevolume (4) and short tips with a small volume (3). Preferred embodimentsof the three parts of racks are described hereinafter.

Upper Rack (1)

Upper rack (1) comprises a frame (50) and a surface plate (51) locatedinside said frame (50) (FIG. 9, FIG. 10). Said surface plate (51)comprises through bore-holes (23, 25) (FIG. 4). On the bottom side (62)of said plate (51), separation walls (16) and separation lamellae (18)are located between through bore-holes (23, 25). They provide additionalprotection against contamination between tips (3, 4) and conferadditional stability on the upper rack (1). Certain separation walls(16) also comprise a recess (13). Said recess (13) allows the separationwalls (15) of the insert rack (14) to engage with separation walls (16)of the upper rack (1) in an overlapping way for sealing againsthorizontal flying drops in case of exploded bubbles during tip handlingwith tip (4). Preferably, separation lamellae (18) with recess (13)alternate with separation lamellae (18) without recess.

Lower Rack (2)

Lower rack (2) comprises two long side walls (52) located opposite eachother, and two short side walls (53) located opposite each other (FIGS.5 and 6). Each short side wall (53) contacts both long side walls (52)to form a frame. The inside space defined by said side walls (52) and(53) comprises chambers (19) which are formed by interior dividing walls(54) with ridge (9) and perpendicular to said walls (54) second walls(55). The chambers (19) comprise bottoms (21) which are preferablyrounded.

Lower rack (2) comprises, on the outside of walls (52) and (53),stacker-guiding elements (6) and (7) which, preferably, are alsohardware identifiers.

Insert Rack (14)

Insert rack (14) comprises two long front walls (56) and two short sidewalls (57). Chambers (24) are formed by separation walls (15) which arearranged parallel to the short side walls (57) (FIG. 7, FIG. 8). Thesechambers (24) have bottoms (58) and can accommodate the second type oftips (3). Between each chamber (24) is a passage way (17) for a firsttype of tip (4) which extends into the chambers (19) of the lower rack(2). Chambers (24) preferably comprise stabilizing ribs (41). The insertrack (14) preferably comprises additional stabilizing ribs (42, 43)

Combo-Tip Rack

The multiple part construction of the rack (60) has several advantages.One advantage is that tips (4) with an elongated shape for pipettinglarge volumes can be stored in independent, closely packed chambers(19). The tips (4), thus, require only a limited space in a horizontalplane for storage, while being able to hold large volumes of liquid.Views of a preferred embodiment are shown in FIGS. 1 to 24.

As a further advantage, the inside horizontal cross section area of thechambers (19) for tips (4) is larger than the cross section of thethrough bore holes of the seating area (22) (FIG. 3). This results in aprevention of capillary forces which may lead to transport of liquidbetween the chambers (19).

Yet another advantage of the construction of the tip rack (60) is thatthe inner walls (54) of the chambers (19) are not continuous from thebottom (21) of the chamber (21) to the seat area (22) (FIG. 3). Thus,the transport of liquid from the bottom (21) of the chamber (21) to theseat area (22), and, thus, contamination is prevented. This makes re-useof the pipette tips (4) possible. In addition, chambers (19) comprise awall (5) located on the inside surface (65) (FIG. 24). Said wall (5)preferably covers only part of the height of chamber (19). Morepreferably, said wall (5) extends from above the bottom (21) of chamber(19) to below ridge (9) of the inside surface (65) of walls (54) of thelower rack (2). Said wall (5) further prevents capillary effects inchamber (19).

Yet another advantage of the construction of the tip rack (60) is thattwo different types of tips can be stored in it (FIG. 3). In the presentpreferred embodiment, a second type of tip (3) is stored in the tip rack(60). The second type of tip is shorter than the first type of tip, andis used to pipette smaller amounts of liquid than is pipetted by thefirst type of pipette tip. In the present preferred example, the secondtype of tips is stored in chambers (24) within the insert rack (14)which are located on a higher level than chambers (19) and arehermetically separated from chambers (19), but are open within one rowof chambers (24). One advantage of this construction is that it is spacesaving. In addition, with the chambers (24) located in the insert rack,there is more space available for preventing contamination, e.g. bycapillary force, between the chambers (19) of the first type of tips(4). In a preferred embodiment, only the first type of tips (4) isre-used, while the second type of tips (3) is used only once.

Insert rack further comprises ridges (8) on the bottom of chambers (24)(FIG. 3). These ridges (8) prevent splashes of liquid which may becaused by blisters of liquid forming on the tip-end of pipette tip (4)and bursting at the height of ridges (8) from passing into theneighboring chambers (19). The lower rack (2) comprises, at the top ofthe walls (54) between chambers (19), a ridge (9). Ridge (9) has thesame function as ridge (8). Ridge (9) and ridge (8) do not contact eachother (FIG. 23). This prevents capillary effects.

When stored in the rack (60), the tips (3, 4) sit on the seating area(22, 26) of a through bore-hole (25, 23) (FIG. 13, FIG. 14). The throughbore-holes (25, 23) are located on a seat area (22, 26). Preferably, theseating area (22) of the through bore-holes (25), is elevated comparedto the seating area (26) of the through bore-holes (23) of the firsttype of tips (4). This has the advantage that when the first type oftips (4) is either replaced in the rack or re-engaged for re-use, incase liquid from the first type of tips (4) contacts the seating area(22) of through bore-hole (25), the liquid can not ascend from the lowerseat area (22) to the higher seat area (26), thus preventingcontamination of the second type of tips (3).

Preferably, additional capillary channels (40) separate neighboringthrough bore-holes (23) at the level of the lower seat area (22) anddrain off any liquid contacting the lower seat area (22) or the throughbore-holes (23) (FIGS. 4, 9, 13, 14). This prevents contamination ofneighboring through bore-holes (23, 25). An additional advantage of thecapillary channels (40) is that the liquid is distributed over a largerarea and can evaporate more quickly.

In a preferred embodiment, the pipette tips comprise a receiving ridge(27, 28) which contacts the seating areas (22, 26) of the throughbore-hole (23, 25) when the pipette tip (3, 4) is seated in the rack(60) (FIG. 15, FIG. 16). More preferably the second type of tips (3) hasa shorter receiving ridge (27) than the first type of tips (4). Thedifference in height between receiving ridge (27) and (28) is equal tothe difference in height of the rim of through bore holes (23) and (25).This has the advantage that all pipette tips (3, 4) are on the samelevel for engagement with the process head (35), but at the same time,the second type of pipette tips (3) can be seated on a higher level onthe rack to prevent contamination by liquid from the first type of tips(4). In addition, it provides a visual control for the correct assemblyof first and second types of pipette tips (3, 4) in the rack (60) sincethe top surface of tips (3, 4) seated in the wrong position would be ata lower or higher level than the correctly seated tips (3, 4).

The receiving ridges (27, 28) on the tip (3, 4) do not comprise acontinuous circumferential seating base (59) for contacting the rim ofthrough bore-hole (23, 25). The seating base (59) only has punctualsites of contact with the seating areas (22, 26). One advantage is thatless material is used for the tip (3, 4) and that the tip (3, 4) can beproduced with higher precision and with less strain. The reduced area ofcontact between the tip (3, 4) and the seating area (22, 26) has theadditional advantage that electrostatic charge of the tips (3, 4) isreduced.

Tips (3, 4) are matted in the area of shaft (29) with a surfaceroughness of 0.8 to 1.6 um, and polished in the area of the tip-end(30). The matted surface of the shaft (29) allows droplets of liquid tolie flat on the surface and to evaporate more quickly. Thus, when tip(4) is inserted into the through bore-hole (23, 25) no or less liquidcan be wiped off if the tip (4) contacts seating area (22, 26), and,thus, the risk of contamination is reduced. The polished tip-end (30)causes droplets of liquid to stay on the tip-end (30) in a pearl-typemanner and to be wiped off the tip-end (30) when the tip (4) submergesfrom a liquid. The tip-end (30), thus, remains without liquid attached.

The upper rack (1) preferably comprises a first type of positioningelements (10) (FIG. 21, FIG. 22) and a second type of positioningelements (31, 32, 33, 34) (FIG. 17, FIG. 18). The first type ofpositioning elements (10) allows an approximate positioning of the rack(60) relative to a process head (35), while the second type ofpositioning elements (31, 32, 33, 34) allows a precise positioning ofsaid rack (60) relative to the process head (35). The approximatepositioning by the first type of positioning elements (10) ensures thatthe second type of positioning elements (31, 33) or (32, 34) are alignedwith counter-positioning elements (36) on the process head (35). Theadvantage of the two types of positioning elements is that thepositioning of rack (60) and process head (35) for tip engagement isfast and precise.

The second type of positioning elements (31, 33) or (32, 34) arepreferably located on the top surface (also referred to as surfaceplate) (51) of the rack (60) (FIGS. 17 to 20). The counter-positioningelements (36) are preferably located on the bottom surface (61) of theprocess head (35).

In a preferred embodiment, the positioning elements (31, 33) engage withcounter-positioning elements (36) on the process head (35) to align thefirst type of pipette tips (4) with the interface on the process head(35) (FIG. 17, FIG. 18). Alternatively, positioning elements (32, 34)engage with counter-elements (36) on the process head (35) to align thesecond type of pipette tips (3) with the interface (67) of the processhead (35) (FIG. 19, FIG. 20).

In a preferred embodiment, the positioning elements are openings (31,32, 33, 34) in the top surface (51) of the rack (60), preferably locatedin opposite corners of the top surface (51) of the rack (FIG. 1). Thecounter-positioning elements, in this preferred embodiment, on thebottom surface (61) of the process head (35) are rods (36) located inthe corresponding corners of the process head (35). Openings (31, 32,33, 34) and rods (36) are constructed such that rods (36) can engagewith openings (31, 32 or 33, 34) for precise alignment of rack (60) andprocess head (35). Thus, the tip (3, 4) and the interface (67) on theprocess head (35) for engagement of the tips (3, 4) are preciselyaligned, and the interface of the process head (35) can engage the tip(3, 4). In a more preferred embodiment, two of the openings (31, 32)have a circular cross-section for precise positioning, in a horizontalplane. Openings (33, 34) have an elongated shape for compensation ofmanufacturing tolerances. This is advantageous because the rack (60) canbe precisely positioned without canting with the process head (35).

The footprint of the rack preferably comprises a length and width of thebase comprises a length and width of the base essentially correspondingto ANSI SBS footprint format. More preferably, the length is 127.76 mm+/−0.25 mm, and the width is 85.48 mm +/−0.25 mm. The rack (60)comprises form locking elements (38) for interacting with a handler(500). The rack (60) can be gripped, transported and positioned quicklyand safely at high speed while maintaining the correct orientation andposition.

The term “essentially corresponding to ANSI SBS footprint format” meansthat the base of any one consumable may have cut out sections, e.g. cutcorners. Thus, the surface geometry of different types of consumableswith ANSI SBS footprint format can be different. However, the base ofany one consumable fits into a station which has a correspondingreceiving part in ANSI SBS footprint format.

The rack (60) comprises one or more hardware-identifiers (39), whereinsaid hardware identifiers (39) are an integral part of the consumable.The rack (60) further comprises stacker guiding elements (6, 7). Saidhardware identifiers (39) and stacker guiding elements (6, 7) compriseridges and/or recesses on the side walls of the consumables, whereinsaid pattern of ridges and/or recesses is unique for a specific type ofconsumable, preferably the rack (60). The stacker guiding elements (6,7) and hardware-identifiers (39) ensure that the user can only load therack (60) into the appropriate stacker position of an analyticalinstrument (46).

The rack (60) also comprises recesses (37) in the side wall of the upperrack (1). The recesses (37) comprise a bottom wall (48) and side walls(49). The rack (60) is positioned inside an opening in an analyticalinstrument (46). When the rack (60) is positioned, the bottom wall (48)of recess (37) contacts the surface of the process deck (47) of theanalytical instrument (46). Said recesses (37) engage with counterelements on an analytical instrument (46) to hold down the rack (60) inthe instrument. This allows for additional stabilization of the rack(60) inside the analytical instrument (46).

The insert rack (14) comprises an external centering surface (11) whichinteracts with internal centering surface (12) on the upper rack (1) toallow centering during assembly of the rack (60) (FIGS. 11, 12; FIGS. 25to 26).

Upper rack (1) and lower rack (2) are fixed during assembly, preferablyby a snap-fit (44) located on either one of two opposite side walls (63,64) of the frame of the upper rack (1) and a snap groove (45) located oneither one of two corresponding opposite side walls of the lower rack(2).

A second embodiment of an exemplary rack is an integral one part tiprack (70) comprising a top surface (71), two opposing short (72) and twoopposing long (73) side walls (FIG. 25). The tip rack comprises vessels(74, 75) for holding pipette tips (3, 4). Said vessels (74, 75) comprisean open top (76) and a closed bottom (77). Any one vessel (74, 75) canhold one tip (3, 4). The footprint of the rack (70) preferably comprisesa length and width of the base essentially corresponding to ANSI SBSfootprint format. More preferably, the length is 127.76 mm +/−0.25 mm,and the width is 85.48 mm +/−0.25 mm. Preferred embodiments of saidsecond embodiment comprise hardware identifiers (6, 7, 39), recesses(37) to engage with counter elements on an analytical instrument to holddown the rack in the instrument as described for the first embodiment ofsaid rack. Preferred embodiments also comprise positioning elements (31,32, 33, 34, 10) as described for the first embodiment of the rack (60).

Positioning of Process Head and Tip Rack

Analytical systems used in the field of diagnostics require processingof samples to be analyzed. Such processing involves transfer of vessels,or of liquid samples and reagents from one vessel to another. For higherthroughput, simultaneous processing is often performed with processingdevices which can handle multiple consumables simultaneously. Engagementof process device and consumables requires proper alignment.

U.S. Pat. No. 6,846,456 discloses an assay work station. Process head(400) is aligned with pipette tips (362) or receptacles (262) which areheld by racks (302) or (202) by engagement of rods (408), (410) locatedon the process head (400) with guide holes (510), (512) located on guidesupports (500). Guide supports and racks are separately mounted on abase structure (100).

The disadvantage of the prior art is that a multitude of positioningsinfluence the alignment of process device and consumable. Imprecisionsof positionings caused by imprecise manufacturing or mounting of thepositioning elements or guide supports with the positioning elements orthe racks (302), (202) can impair the precision of the alignment ofprocess device and consumable.

A positioning method for aligning a rack and a process device is alsodisclosed. The positioning method comprises aligning at least twopositioning elements located on the bottom surface of said processdevice with at least two positioning elements located on the top surfaceof said rack, and mechanically engaging said positioning elements on theprocess device with the positioning elements of the rack. Processdevices preferably relate to pipettor for engaging with pipette tips topipette liquids. Such process heads are well known in the art.

Preferably, said consumable is a tip rack comprising pipette tips, andsaid process device is a process head comprising an interface forengaging with pipette tips. The pipette tips are preferably arranged ina 2-dimensional array in said pipette rack.

The engagement of the positioning elements on the process device and thepositioning elements on the consumable cause the interface of theprocess device to interact and engage with the pipette tips.

A “rack” is understood to be any type of device used in an analyticalsystem which holds a sample, a device which holds a consumable which isconstructed and arranged to hold a sample. The rack has a top surfaceand four sidewalls, wherein two side walls are parallel and opposingeach other. Optionally, the rack also has a bottom surface. A consumableis understood to be a device which is introduced recurrently to theanalytical system for use in an analytical test. A consumable may beused a single time before being replaced, or it may be use multipletimes. In one preferred embodiment, said rack holds vessels. Saidvessels can hold a sample for use in an analytical system. Said sampleis understood to relate to a sample to be processed in an analyticalsystem, or a reagent to be used in an analytical system. Alternatively,said vessels are pipette tips for aspirating and dispensing liquids.Said liquids may be samples or reagents as defined hereinbefore. Thus,said rack may be a pipette tip rack. Preferred embodiments of saidpipette tip rack include integrally formed racks or racks comprisingmore than one part, as shown in FIG. 25 or 1. A multiple part rack isdescribed herein as a preferred, but not limiting example. In anotherpreferred embodiment, the rack is a multiwell plate comprising vesselsintegrally attached to said rack.

A process device is any type of device used in an analytical systemwhich is involved in the processing of a sample during an analyticaltest, and which requires alignment with a sample device. A preferredembodiment of a process device is a process head. A process head isunderstood to be a device which engages with pipette tips. Said devicecomprises an interface which can engage with said pipette tips.Preferably, said interface comprises cones. However, other interfacesknown in the art are also included. In other embodiments, said processdevice may also include devices for gripping consumables. Preferredembodiments of interfaces are cones, cylindrical interfaces orinterfaces with O-rings.

Positioning elements are understood to be elements located on theprocess device and on the rack. Said elements are constructed andarranged such that positioning elements on the process device caninteract with positioning elements on the rack, thereby mechanicallyengaging the process device and the rack.

The process head preferably comprises a number of interfaces equal tothe number of pipette tips of a first type. The process head canselectively engage with pipette tips of a first type or pipette tips ofa second type. To achieve this, at least two positioning elements on thetip rack engage with at least two positioning elements on the processhead such that the process head only engages with pipette tips of afirst or with pipette tips of a second type. The selective engagementwith pipette tips of different types can also be accomplished with a tiprack which comprises more than two types of pipette tips simply bychoosing the appropriate number of positioning elements on the tip rack.

Preferably, one positioning element on the rack located in one cornerhas a first shape and the second positioning element on the rack whichis mounted on the diagonally opposite corner of said top surface of saidtip rack has a second shape. More preferably, the first shape is acircular cross-section and the second shape is an elongated shape. Theadvantages of this embodiment are further described below. In order toachieve a more reliable positioning, the method may also include a firstpositioning step, wherein the positioning elements located on the bottomsurface of said process device and the positioning elements located onthe top surface of said rack are aligned. Preferably, the firstpositioning is mediated by engagement of said positioning element with anotch.

Further preferred embodiments of the method disclosed herein aredescribed hereinbefore and hereinafter.

In a preferred embodiment of the positioning method hereinbeforedescribed, said tip rack (60, 70) comprises alternating rows of pipettetips of a first type (4) and pipette tips of a second type (3).

Preferably, said process head (35) comprises a number of interfaces (67)equal to the number of pipette tips of a first type (4). Said interfaces(67) may be conical or cylindrical, and may preferably comprise anO-ring. More preferably, at least two positioning elements (31, 32, 33,34) on the tip rack (60, 70) engage with at least two positioningelements (36) on the process head (35) such that the process head (35)only engages with pipette tips of a first (4) or with pipette tips of asecond (3) type. Further more preferably, said method additionallycomprises a first positioning step, wherein the positioning elements(36) located on the bottom surface (61) of said process device (35) andthe positioning elements (31, 32, 33, 34) located on a top surface (66)of said rack (60, 70) are aligned. Further preferred, said firstpositioning is mediated by engagement of a positioning element (10) witha notch (20). In a more preferred embodiment, said positioning elements(36) on the process device are pins, and said positioning elements (31,32, 33, 34) on the top surface (66) of said rack are openings which aresized to engage with the pins. In a most preferred embodiment, the tiprack (60, 70) comprises four positioning elements (31, 32, 33, 34) andthe process head (35) comprises two positioning elements (36).

In a preferred embodiment of the method hereinbefore described, saidpositioning elements (31, 32, 33, 34, 36) are located in diagonallyopposite corners of said process device (35) or said rack (60, 70).However, other locations may be envisioned which lead to a similarresult. Preferably, the tip rack (60, 70) comprises an equal number offirst pipette tips (4) and second pipette tips (3). Most preferably, onepositioning element (31, 32) on the rack (60, 70) located in one corneris a circular opening, and the corresponding second positioning element(33, 34) on the rack which is mounted on the diagonally opposite cornerof the top surface of said tip rack (60, 70) is an oval opening.

Handler

A method for isolating and processing an analyte that may be present ina fluid sample is disclosed. The method comprises the automated stepsof:

-   -   a) providing a fluid sample in a multiwell vessel in a first        station;    -   b) combining together a solid support material and said fluid        sample in a well of said multiwell vessel for a period of time        and under conditions sufficient to permit said analyte to be        immobilized on the solid support material;    -   c) isolating the solid support material from other material        present in the fluid sample in a separation station;    -   d) and purifying the analyte in the separation station by        separating the fluid sample from the solid support material and        washing the materials one or more times with a wash buffer;    -   wherein said multiwell vessel is contacted by a handler and        wherein said multiwell vessel is transported between stations by        said handler, wherein said contact between said handler and said        multiwell vessel is a form-locking contact.

Preferably, said multiwell vessel is a multiwell plate. Preferably, themethod additionally comprises the step of analyzing the purified analytein a analyzing station. More preferably, the analyzing is performed in asecond multiwell plate.

Even more preferably, said second multiwell plate is contacted by atleast one handler, preferably a handler, and transported betweenstations, wherein said contact between said handler and said multiwellvessel is a form-locking contact. Furthermore, the handler preferablytransports the multiwell vessel between two stations, or between threestations. Said stations are preferably a storage station and/or a samplestation and/or a separation station and/or a holding station and/or asealing station and/or an analyzing station, and/or a detection station.

In a preferred embodiment, the method additionally comprises the step ofproviding pipette tips in a tip rack, wherein said tip rack is contactedby at least one handler and transported between stations, wherein saidcontact between said at least one handler and said tip rack vessel is aform-locking contact. One of the stations is preferably a storagestation. Other preferred stations are the stations described herein.

In a preferred embodiment, said analyzing station is an amplificationstation. Preferably, the amplification station is an amplification anddetection station. Preferably, the method additionally comprises thestep of combining said purified nucleic acid with reagents sufficientfor amplifying said analyte in a vessel of a multiwell plate, whereinsaid multiwell plate is held in a holding station. In a more preferredembodiment, one handler transports a multiwell vessel from a holdingstation to an air-lock (460), and a second handler transports saidmultiwell plate from said air-lock to said amplification station,wherein both handlers interact with said multiwell plate by aform-locking interaction.

In a preferred embodiment, said handler comprises gripper fingers,wherein said gripper fingers fit with a recess of the multiwell plate,wherein said fit is form-locking. (FIGS. 48, 49).

A system for purifying and analyzing an analyte is, furthermore,disclosed, comprising a processing cell comprising a separation stationfor separating an analyte comprised in a vessel of a multiwell platefrom a solid support material. Preferably, said separation station isconstructed and arranged to separate an analyte comprised in a vessel ofa multiwell plate from a solid support material. The system furthercomprises an analyzing cell comprising an analyzing station, whereinsaid station comprises an incubator to process said analyte to generatea signal indicative of the presence or absence of said analyte.Additionally, the system comprises more than one consumable comprisingopenings wherein at least one opening is located on one side wall of theconsumable and at least one opening is located on the opposing side wallof the consumable. A gripper system comprising at least one handler isalso comprised in the system, wherein said at least one handlercomprises at least one gripper finger on one side of the handler, and atleast one gripper finger on the opposing side of the handler. Saidgripper fingers interact with said openings on the consumables andwherein said interaction is a form-locking interaction. Preferably, thesystem hereinbefore described additionally comprises a sample cellconstructed and arranged to transfer a liquid sample from a samplevessel to a multiwell vessel. In a preferred embodiment, the multiwellvessel is transported between cells with said gripper system. In afurther preferred embodiment, the multiwell vessel is transported fromsaid sample cell to said analyzing cell. Preferred consumables aredescribed herein. Preferably, said more than one consumables comprise amultiwell plate and a tip rack.

A preferred handler (500) comprises a central part (500 a) which isconnected to a robotic arm (502). The central part (500 a) comprises, ontwo opposite sides, gripper fingers (501). The gripper fingers (501) aremovable. When engaging with a consumable (60, 70, 101, 301, 302)comprising form-locking elements (38, 106, 507, 309), as hereinbeforedescribed, the gripper fingers (501) connect with the consumable (60,70, 101, 301, 302). The gripper fingers (501) are moved towards theconsumable (60, 70, 101, 301, 302), in X-direction, interlock with theform locking elements (38, 106, 507, 309), until the gripper fingers(501) reach a stop. In this position, a form-locked position betweenhandler (500) and consumable (60, 70, 101, 301, 302) exists. The handler(500) connected to the robotic arm (502) can move the consumable (60,70, 101, 301, 302) from one position to a second position. To releasethe consumable (60, 70, 101, 301, 302), the gripper fingers (501) moveaway from the consumable (60, 70, 101, 301, 302). Preferably, thehandler comprises spring-mounted pins (506). Said pins (506) are forcedaway from the consumable (60, 70, 101, 301, 302) when the handler (500)is pushed on the consumable (60, 70, 101, 301, 302). In this position,the gripper fingers (501) can interact with the form locking elements(38, 106, 507, 309) of the consumable (60, 70, 101, 301, 302). Whenpressing the handler (500) down on the consumable (60, 70, 101, 301,302), the gripper fingers (501) can move away from the form lockingelements (38, 106, 507, 309) of the consumable (60, 70, 101, 301, 302)(FIG. 50 (a)).

The handler (500) also comprises pins (507) which are located sidewaysof the multiwell plate when the handler (500) is moved downwards on theconsumable (60, 70, 101, 301, 302) prior to gripping. These pins (507)guide the consumable (60, 70, 101, 301, 302) into the correct positionfor gripping. Furthermore, said pins (507) prevent the consumable (60,70, 101, 301, 302) from getting stuck to the handler (500) when thegripper fingers (501) move away from the consumable (60, 70, 101, 301,302) (FIG. 50 (b)).

Preferably said form-locking elements (38, 106, 507, 309) are openings(38, 106, 507, 309) in the side walls of the consumable, more preferablythe long side of the consumable (60, 70, 101, 301, 302). Preferably, twoopenings (38, 106, 507, 309) are located on one side wall, and twoopenings (38, 106, 507, 309) are located on the opposite side wall.

Multiwell Plate/Processing Plate

A multiwell plate for incubating or separating an analyte is disclosed.Multiwell plates are preferably used in analytical systems. They allowparallel separation and analyzing or storage of multiple samples.Multiwell plates may be optimized for maximal liquid uptake, or formaximal heat transfer.

An improved multiwell plate for optimal use in an automated analyticalsystem is provided.

The multiwell plate is optimized for incubating or separating an analytein an automated analyzer. Preferably, the multiwell plate is constructedand arranged to contact a magnetic device and/or a heating device.

Said multiwell plate comprises:

a top surface comprising multiple vessels with openings at the toparranged in rows. The vessels comprise an upper part, a center part anda bottom part. The upper part is joined to the top surface of themultiwell plate and comprises two longer and two shorter sides. Thecenter part has a substantially rectangular cross-section with twolonger sides and two shorter sides;

two opposing shorter and two opposing longer side walls; and

a base, wherein said base comprises an opening constructed and arrangedto place the multiwell plate in contact with said magnetic device and/ora heating device.

In a preferred embodiment of the multiwell plate, adjacent vesselswithin one row are joined on the longer side of said almost rectangularshape.

Preferably, the multiwell plate comprises a continuous space which islocated between adjacent rows of vessels. Said continuous space isconstructed and arranged to accommodate a plate-shaped magnetic device.In a preferred embodiment, the bottom part of the vessels comprises aspherical bottom. In a more preferred embodiment, the bottom part ofsaid vessels comprises a conical part located between said central partand said spherical bottom.

In a preferred embodiment, the top surface comprises ribs, wherein saidribs surround the openings of the vessels. Preferably, one shorter sideof said upper part of the vessels comprises a recess, said recesscomprising a bent surface extending from the rib to the inside of thevessel.

Furthermore, in a preferred embodiment, the vessels comprise a roundedinside shape.

For fixation to the processing or incubation stations, the basepreferably comprises a rim comprising recesses. Latch clips on a stationof an analyzer can engage with said recesses to fix the plate on astation.

In a preferred embodiment, the vessels comprise an essentially constantwall thickness.

The processing plate (101) is preferably a 1-component plate. Its topsurface (110) comprises multiple vessels (103) (FIG. 28, FIG. 29). Eachvessel has an opening (108) at the top and is closed at the bottom end(112). The top surface (110) comprises ribs (104) which are preferablyelevated relative to the top surface (110) and surround the openings(108) of the vessels (103). This prevents contamination of the contentsof the vessels (103) with droplets of liquid that may fall onto the topsurface (110) of the plate (101). Views of a preferred process plate areshown in FIGS. 26 to 37.

The footprint of the processing plate (101) preferably comprises alength and width of the base corresponding to ANSI SBS footprint format.More preferably, the length is 127.76 mm +/−0.25 mm, and the width is85.48 mm +/−0.25 mm. Thus, the plate (101) has two opposing shorter sidewalls (109) and two opposing longer side walls (118). The processingplate (101) comprises form locking elements (106) for interacting with ahandler (500). The processing plate (101) can be gripped, transportedand positioned quickly and safely at high speed while maintaining thecorrect orientation and position. Preferably, the form locking elements(106) for gripping are located within the upper central part, preferablythe upper central third of the processing plate (101). This has theadvantage that a potential distortion of the processing plate (101) hasonly a minor effect on the form locking elements (106) and that thehandling of the plate (101) is more robust.

The processing plate (101) preferably comprises hardware-identifiers(102) and (115). The hardware identifiers (102) and (115) are unique forthe processing plate (101) and different from hardware identifiers ofother consumables used in the same system. The hardware identifiers(102, 115) preferably comprise ridges (119) and/or recesses (125) on theside walls of the consumables, wherein said pattern of ridges (119)and/or recesses (125) is unique for a specific type of consumable,preferably the processing plate (101). This unique pattern is alsoreferred to herein as a unique “surface geometry”. Thehardware-identifiers (102, 115) ensure that the user can only load theprocessing plate (101) into the appropriate stacker position of ananalytical instrument (126) in the proper orientation. On the sides ofprocessing plate (101), guiding elements (116) and (117) are comprised(FIG. 33). They prevent canting of the processing plate (101). Theguiding elements (116, 117) allow the user to load the processing plates(101) with guiding elements (116, 117) as a stack into an analyticalinstrument which is then transferred vertically within the instrument ina stacker without canting of the plates.

The center part (120) of the vessels (103) has an almost rectangularcross section (FIG. 30, FIG. 31). They are separated along the longerside (118) of the almost rectangular shape by a common wall (113) (FIG.37). The row of vessels (103) formed thereby has the advantage thatdespite the limited space available, they have a large volume,preferably of 4 ml. Another advantage is that because of the essentiallyconstant wall thickness, the production is very economical. A furtheradvantage is that the vessels (103) strengthen each other and, thus, ahigh stability of the shape can be obtained.

Between the rows (123) of vessels (103), a continuous space (121) islocated (FIG. 31, FIG. 35). The space (121) can accommodate magnets(122) or heating devices (128) (FIG. 36, FIG. 38). These magnets (122,127) and heating devices (128) are preferably solid devices. Thus,magnetic particles (216) comprised in liquids (215) which can be held inthe vessels (103) can be separated from the liquid (215) by exerting amagnetic field on the vessels (103) when the magnets (122, 127) arebrought into proximity of the vessels (103). Or the contents of thevessels (103) can be incubated at an elevated, controlled temperaturewhen the processing plate (101) is placed on the heating device (128).Since the magnets (122, 127) or heating devices (128) can be solid, ahigh energy density can be achieved. The almost rectangular shape of thecentral part (120) of the vessels (103) (FIG. 36, FIG. 37) alsooptimizes the contact between the vessel wall (109) and a flat shapedmagnet (122) or heating device (128) by optimizing the contact surfacebetween vessel (103) and magnet (122) or heating device (128) and thusenhancing energy transfer into the vessel (103).

In the area of the conical bottom (111) of the vessels, the space (121)is even more pronounced and can accommodate further magnets (127). Thecombination of the large magnets (122) in the upper area and the smallermagnets (127) in the conical area of the vessels (3) allows separationof magnetic particles (216) in larger or small volumes of liquid (215).The small magnets (127), thus, make it easier to sequester the magneticparticles (216) during eluate pipetting. This makes it possible topipette the eluate with minimal loss by reducing the dead volume of themagnetic particle (216) pellet. Furthermore, the presence of magneticparticles (216) in the transferred eluate is minimized.

At the upper end of the vessels (103), one of the shorter side walls(109) of the vessel (103) comprises an reagent inlet channel (105) whichextends to the circumferential rib (104) (FIG. 32, FIG. 30). Thereagents are pipetted onto the reagent inlet channel (105) and drain offthe channel (105) into the vessel (103). Thus, contact between thepipette needle (80) or tip (3, 4) and liquid contained in the vessel isprevented. Furthermore, splashes resulting from liquid being directlydispensed into another liquid (215) contained in the vessels (103),which may cause contamination of the pipette needle (80) or tip (3, 4)or neighboring vessels (103) is prevented. Sequential pipetting onto thereagent inlet channel (105) of small volumes of reagents followed by thelargest volume of another reagent ensures that the reagents which areonly added in small amounts are drained completely into the vessel(103). Thus, pipetting of small volumes of reagents is possible withoutloss of accuracy of the test to be performed.

On the inside, on the bottom of the vessels (111, 112), the shapebecomes conical (111) and ends with a spherical bottom (112) (FIG. 34).The inside shape of the vessel (114), including the rectangular centerpart (120), is rounded. The combination of spherical bottom (112),rounded inside shape (114), conical part (111) and refined surface ofthe vessels (103) leads to favorable fluidics which facilitate aneffective separation and purification of analytes in the processingplate (101). The spherical bottom (112) allows an essentially completeuse of the separated eluate and a reduction of dead-volume which reducesthe carryover of reagents or sample cross-contamination.

The rim on the base (129) of the processing plate (101) comprisesrecesses (107) for engagement with latch clips (124) on the processingstation (201) or heating device (128) or analytical instrument (126)(FIG. 28, FIG. 38, FIG. 39). The engagement of the latch clips (124)with the recesses (107) allows positioning and fixation of theprocessing plate (101) on the processing station (201). The presence ofthe recesses (107) allows the latch force to act on the processing plate(101) almost vertically to the base (129). Thus, only small forcesacting sideways can occur. This reduces the occurrence of strain, and,thus, the deformation of the processing plate (101). The vertical latchforces can also neutralize any deformations of the processing plate(101) leading to a more precise positioning of the spherical bottoms(111) within the processing station (201). In general, the preciseinterface between the processing plate (101) and the processing station(201) or heating device (128) within an analyzer (126) reducesdead-volumes and also reduces the risk of sample cross-contamination.

Separation Station

A device for separating an analyte bound to magnetic particles in aliquid contained in a vessel is disclosed. The device comprises amultiwell plate comprising vessels with an opening at the top surface ofthe multiwell plate and a closed bottom. The vessels comprise an upperpart, a center part and a bottom part, wherein the upper part is joinedto the top surface of the multiwell plate and preferably comprises twolonger and two shorter sides. The center part has a substantiallyrectangular cross-section with two longer sides, wherein said vesselsare aligned in rows. A continuous space is located between two adjacentrows for selectively contacting at least one magnet mounted on a fixturewith the side walls in at least two Z-positions. The device furthercomprises a magnetic separation station comprising at least one fixture.The fixture comprises at least one magnet generating a magnetic field. Amoving mechanism is present which vertically moves said at least onefixture comprising at least one magnet at least between first and secondpositions with respect to the vessels of the multiwell plate.Preferably, said at least two Z-positions of the vessels comprise theside walls and the bottom part of said vessels. The magnetic field ofsaid at least one magnet preferably draws the magnetic particles to aninner surface of the vessel adjacent to said at least one magnet whensaid at least one magnet is in said first position. The effect of saidmagnetic field is less when said at least one magnet is in said secondposition than when said at least one magnet is in said first position.Preferably, the fixture comprising said at least one magnet comprises aframe. The vessels have preferred features as described under Multiwellplate/Processing plate. One such preferred feature is that at least apart of said vessels has a substantially rectangular cross-sectionorthogonal to the axis of said vessels.

In said first position, said at least one magnet is adjacent to saidpart of said vessels. Adjacent is understood to mean either in closeproximity such as to exert a magnetic field on the contents of thevessel, or in physical contact with the vessel.

The separation station comprises a frame to receive the multiwell plate,and latch-clips to attach the multiwell plate. Preferably, theseparation station comprises two types of magnets. This preferredembodiment is further described below.

A second preferred embodiment is described below, which comprises aspring which exerts a pressure on the frame comprising the magnets suchthat the magnets are pressed against the vessels of the multiwell plate.

The first magnets are preferably constructed and arranged to interactwith vessels of a multiwell plate for exerting a magnetic field on alarge volume of liquid comprising magnetic particles held in saidvessels. Said second magnets preferably are constructed and arranged tointeract with vessels of a multiwell plate for exerting a magnetic fieldon a small volume of liquid comprising magnetic particles held in saidvessels. Said first and second magnets can be moved to differentZ-positions.

A method of isolating and purifying an analyte, preferably a nucleicacid is disclosed. The method comprises the steps of binding an analyteto magnetic particles in a vessel of a multiwell plate. The vesselcomprises an upper opening, a central part and a bottom part. The boundmaterial is then separated from unbound material contained in a liquidwhen the major part of the liquid is located above the section where theconical part of the vessel is replaced by the central part with therectangular shape, by moving a magnet from a second position to a firstposition and, in said first position, applying a magnetic field to thecentral part and, optionally, additionally applying a magnetic field tothe bottom part of said vessel. The magnetic particles can optionally bewashed with a washing solution. A small volume of liquid, wherein themajor part of the liquid is located below the section where the conicalpart of the vessel is replaced by the central part with the rectangularshape is separated from said magnetic particles by selectively applyinga magnetic field to the bottom part of said vessel.

The method hereinbefore described preferably additionally comprisesbetween steps c) and d) the step of eluting said nucleic acid.Preferably, the method comprises the step of transferring said eluatefrom a said multiwell plate to a second multiwell plate. In a furtherpreferred embodiment, in step b), a first type of magnet is moved from asecond position to a first position to apply a magnetic field to acentral part of the vessel, and, optionally, a second type of magnet ismoved to the bottom part of the vessel to apply a magnetic field. Morepreferably, a magnet is moved to the central part of the vessel for stepb), and the magnet is moved to the bottom part of said vessel into athird position for eluting said nucleic acid.

A magnetic separation station for separating an analyte bound tomagnetic particles is disclosed, said separation station comprisingfirst magnets which are constructed and arranged to interact withvessels of a multiwell plate for exerting a magnetic field on a largevolume of liquid comprising magnetic particles held in said vessels, andsecond magnets constructed and arranged to interact with vessels of amultiwell plate for exerting a magnetic field on a small volume ofliquid comprising magnetic particles held in said vessels, and whereinsaid first and second magnets can be moved to different Z-positions.Preferred embodiments of the magnetic separation station are describedherein.

A first preferred embodiment of a separation station (201) is describedbelow. The first preferred embodiment of said separation station (201)comprises at least two types of magnets (202, 203). The first, long typeof magnet (202) is constructed and arranged to fit into the space (121)of the processing plate (101). Magnet (202), thus, exerts a magneticfield on the liquid (215) in the vessel (103) to sequester magneticparticles (216) on the inside of the vessel wall. This allows separationof the magnetic particles (216) and any material bound thereto and theliquid (215) inside the vessel (103) when a large volume of liquid (215)is present. Magnet (202) has an elongated structure and is constructedand arranged to interact with the essentially rectangular central part(120) of the vessel. Thus, magnet (202) is used when the major part ofthe liquid (215) is located above the section where the conical part(111) of the vessel (103) is replaced by the central part (120) with therectangular shape. As shown in FIG. 40, the preferred construction ofthe magnets (202) comprises fixtures (204, 204 a) comprising magnets(202) which fit into the space (121) between the rows of vessels (103)in the processing plate (101). Another preferred embodiment of magnets(202) comprises magnets (202) arranged on fixtures (204, 204 a). Themagnets (203) of the preferred separation station (201) are smaller, andcan interact with the conical part (111) of the vessel (103). This isshown in FIG. 41 (a). Magnets (203) are preferably arranged on a base(205) which can be moved into the space (121) of the processing plate(101). Each magnet (202, 203) is preferably constructed to interact withtwo vessels (103) in two adjacent rows. In a preferred embodiment, theprocessing plate (101) has 6 rows of 8 vessels (103). A separationstation (201) which can interact with the preferred processing plate(101) has three fixtures (204, 204 a) comprising magnets (202) and fourbases (205) comprising magnets (203). An embodiment is also includedwherein the separation station has four magnetic fixtures (204, 204 a)comprising magnets (202) and three magnetic bases (205) comprisingmagnets (203).

The magnets (202, 203) are movable. The separation station (201)comprises a mechanism to move the fixtures (204, 204 a) and the bases(205). All fixtures (204, 204 a) are interconnected by a base (217) andare, thus, moved coordinately. All magnets (203) are joined to one base(218) and are, thus, moved coordinately. The mechanism for moving themagnetic plates (202) and (203) is constructed and arranged to move thetwo types of magnetic plates (202, 203) to a total of four endpositions.

In FIGS. 40 a-c, the magnets (203) are located in proximity of theconical part of the vessels (103) of the processing plate (101). This isthe uppermost position of magnets (203), and is the separation position.In this Figure, the magnets (202) are located in the lowermost position.They are not involved in separation when they are in this position.

In FIGS. 41 a-c, the magnets (202) and (203) are in their lowermostposition. None of the magnets is in a separation position. Therefore, inthis position, no separation of magnetic particles from liquid canoccur.

FIGS. 42 a-c show a position in which the magnets (202) are located inthe space (121) of the processing plate (101). This is the highestZ-position of magnets (202). In this Figure, the magnets (203) are alsolocated in the highest Z-position. They exert a magnetic field on theliquid in the conical area of the vessels (103). Thus, both magnets arein a separation position. The highest Z-position of magnets (202) and(203) are, thus, different.

FIGS. 43 a-c show a position in which the magnets (202) are located inthe space (121) of the processing plate (101). This is the uppermostposition of magnets (202), and is the separation position. In thisFigure, the magnets (203) are located in the lowermost position. Theyare not involved in separation when they are in this position.

In the preferred embodiment shown in FIGS. 40 to 43, the base (217) ofmagnets (202) is connected to a positioning wheel (206). The base (217)comprises a bottom end (207) which is flexibly in contact with aconnecting element (208) by a moving element (209). Said moving elementis constructed and arranged to move the connecting element (208) along arail (212) from one side to the other. Said moving element (209) isfixed to the connecting element (208) with a pin (220). Said connectingelement (208) is fixed to the positioning wheel (206) by screw (210).Connecting element (208) is also connected to axis (211). Saidconnecting element (208) is preferably a rectangular plate. As thepositioning wheel (206) moves eccentrically, around an axis (211), suchthat the screw (210) moves from a point above the eccentric axis to apoint below the eccentric axis, moving element (209) and the bottom end(207) of the base (204) with the magnets (202) attached thereto aremoved from the uppermost position to the lowermost position. The base(218) is mounted on a bottom part (219) and is connected, at its lowerend, with pin (213) to a moving element (214), which is preferably awheel, which interacts with the positioning wheel (206). When thepositioning wheel (206) rotates around the axis (211), wheel (214) movesalong positioning wheel (206). If the wheel (214) is located on asection of positioning wheel (206) where the distance from the axis(211) is short, the magnets (203) are in their lowermost position. Whenwheel (214) is located on a section of positioning wheel (206) where thedistance from the axis (211) is at, a maximum, the magnets (203) are intheir uppermost position. Thus, in the preferred embodiment of the firstembodiment of the separation station, the location of the magnets (203)is controlled by the shape of the positioning wheel (206). When movingelement (209) moves along the central, rounded upper or lower part (212a) of rail (212), the small type of magnets (203) are moved up and down.When the moving element (209) is located on the side (212 b) of bottomend (207) and moves up or down, the magnets (202) are moved up- ordownwards. The positioning wheel can be rotated by any motor (224).

In a preferred embodiment, a spring (225) is attached to the base (222)of the separation station and the base (218) of magnets (203) to ensurethat magnets (203) are moved into the lowermost position when they aremoved downwards.

The term “pin” as used herein relates to any fixation element, includingscrews or pins.

In a second preferred embodiment, the separation station (230) comprisesat least one fixture (231) comprising at least one magnet (232),preferably a number of magnets equal to a number of vessels (103) in arow (123). Preferably, the separation station (230) comprises a numberof fixtures (231) equal to the number of rows (123) of the multiwellplate (101) hereinbefore described. More preferably, six fixtures (231)are mounted on the separation station (230). At least one magnet (232)is mounted on one fixture (231). Preferably, the number of magnets (232)equals the number of vessels (103) in one row (123). Most preferably,eight magnets (232) are mounted on one fixture (231). Preferably, onetype of magnet (232) is comprised on said fixture (231). Morepreferably, the magnet (232) is mounted on one side of the which isoriented towards the vessels with which the magnet interacts.

The fixture (231) is mounted on a base (233). Preferably, said mount isflexible. The base (233) comprises springs (234) mounted thereon. Thenumber of springs (234) is at least one spring per fixture (231) mountedon said base (233). The base further comprises a chamfer (236) whichlimits the movement of the spring and, consequently, the fixture (231)comprising the magnets (232). Preferably, any one of said springs (234)is constructed and arranged to interact with a fixture (231). Morepreferably, said spring (234) is a yoke spring. Said interactioncontrols the horizontal movement of the fixtures (231). Furthermore, theseparation station (230) comprises a frame (235). The base (233) withfixtures (231) is connected to the frame (235) by a moving mechanism asdescribed hereinbefore for the magnets (232) of the first embodiment.

Preferably, said base (233) and fixture (231) is constructed andarranged to move vertically (in Z-direction).

The multiwell plate (101) hereinbefore described is inserted into theseparation station (230). The fixture (231) comprising the magnets (232)is moved vertically. Any one fixture (232) is, thus, moved into a space(121) between two rows (123) of vessels (103). The vertical movementbrings the magnets (232) mounted on a fixture (231) into contact withthe vessels (103). The Z-position is chosen depending on the volume ofliquid (215) inside the vessels (103). For large volumes, the magnets(232) contact the vessels (103) in a center position (120) where thevessels (103) are of an almost rectangular shape. For small volumes ofliquid (215) where the major part of the liquid (215) is located belowthe center part (120) of the vessels (103), the magnets (232) preferablycontact the conical part (111) of the vessels (103).

A spring is attached to the base (233) of any one frame (231) (FIGS. 39(a), (b)). The spring presses the magnets (232) against the vessels(103). This ensures a contact between magnets (232) and vessels (103)during magnetic separation. Preferably, the magnet (232) contacts thevessel (103) on the side wall (109) located underneath the inlet (105).This has the advantage that liquid which is added by pipetting flowsover the sequestered magnetic particles and ensures that particles areresuspended and that all samples in all vessels are treated identically.

This embodiment is particularly suited to separate a liquid (215)comprised in a multiwell plate (101) as hereinbefore described, frommagnetic particles (216) when different levels of liquid (215) arecontained in the vessels (103) of said multiwell plate (101).

AD Plate and Frame

For amplification and detection, multiwell plates are commonly used.Such plates are particularly useful in automated analytical systemswhich comprise an amplification station for amplifying nucleic acidanalytes.

In order to prevent contamination between wells prior to, during andafter the amplification reaction, reaction vessels in whichamplification takes place are sealed. A common way of sealing foramplification multiwell plates comprises placing a sealing foil on theplate and connecting it to the plate, either by gluing or by heatsealing.

An improved automated method for isolating and amplifying a nucleicacid, improved multiwell plate with a sealing foil and improvedautomated analytical system are disclosed herein.

A method for isolating and amplifying a nucleic acid analyte that may bepresent in a fluid sample is disclosed. The method comprises separatingsaid nucleic acid analyte from other material present in said fluidsample in a first vessel. Preferably, said first vessel is comprised ina first multiwell plate. A second multiwell plate is provided. Thissecond multiwell plate comprises a lid which comprises a frame and asealing foil. The lid is lifted and then the separated analyte in thefirst vessel is transferred to a well of the second multiwell plate. Thelid comprising said sealing foil is placed on the second multiwellplate. Then the second multiwell plate is sealed with the sealing foil.Once the second multiwell plate is sealed, the analyte is amplified inthe presence of amplification reagents which were added prior tosealing, in said second multiwell plate.

In a preferred embodiment, in step b), the lid is present on the secondmultiwell plate in a first position, said first position preventingcontact between the sealing foil and the multiwell plate; and in stepe), the lid is placed on said second multiwell plate in a secondposition, wherein said second position promotes contact between saidsealing foil and said multiwell plate.

In a preferred embodiment of the method hereinbefore described, the lidis rotated by 180°.

Preferably, the frame comprises supporting ribs, more preferably foursupporting ribs, and the multiwell plate comprises correspondingrecesses, more preferably four corresponding recesses, wherein saidrecesses are positioned such that the supporting ribs of the frame donot align with the recesses in the first position of the lid on themultiwell plate, and that the supporting ribs do align with the recessesin the second position of the lid on the multiwell plate.

In said second position, the supporting ribs of the frame are preferablyplaced within the recesses of the multiwell plate.

In one preferred embodiment of the method described herein, the sealingin step f) is heat sealing. Further preferred embodiments of the methodare described hereinbefore or hereinafter.

A multiwell plate set comprising a multiwell plate and a lid isdisclosed, wherein said lid comprises a frame and a sealing foil affixedto said frame, wherein in a first position of said lid on said multiwellplate, a separation distance is located between said sealing foil andthe top surface of said multiwell plate, and in a second position, thesealing foil is in contact with said top surface of the multiwell plate.Preferably, the frame comprises supporting ribs and the multiwell platecomprises openings, wherein, in said first position, the supporting ribsare in a different location than the openings, and in said secondposition, said supporting ribs and said openings align. In a preferredembodiment of the multiwell plate set herein described, the top surfaceof said multiwell plate comprises heat rims, and in said secondposition, the sealing foil contacts the heat rims. Preferably, thesealing foil is affixed to the frame by a heat sealing method. Morepreferably, the sealing foil is affixed to the top surface of the frame.In a preferred embodiment, the sealing foil comprises a polymer.Preferably, the sealing foil comprises at least two layers withdifferent melting points. More preferably, the sealing foil comprisestwo layers with different melting points, wherein the layer with thelower melting point is oriented towards the multiwell plate. Furtherpreferred embodiments of the method are described hereinbefore orhereinafter.

An analytical system comprising a holding station and a multiwell plateas described herein is also disclosed, wherein said multiwell plate isfixed in said holding station.

Preferably, the analytical system additionally comprises a sealingstation for heat-sealing of the sealing foil comprised in the frame tothe multiwell plate.

Preferably, the multiwell plate comprises a base with a rim whichcomprises recesses, wherein a positioning and fixing element on saidholding station contacts said recesses, wherein said contact exerts adownwards pressure on the base of the multiwell plate, thereby fixingthe multiwell plate in the holding station.

The exemplary multiwell plate with a frame comprises a multiwell plate(300) which comprises a multitude of vessels (312). Said vessels (312)are integrally formed on the upper surface (326) of the multiwell plate(301). On the upper surface (326) each vessel (312) is surrounded by anelevated heat rim (311). The lid (302) comprises a frame (302 b)comprising a polymer (314) and a foil (303) comprising a polymer. Thefoil (303) is affixed to the frame (302 b) by a heat sealing method.Preferably, the foil (303) is sealed onto the top surface (302 a), morepreferably by heat sealing.

The multiwell plate (300) comprises two long side walls (323, 324) whichare opposite each other, and two short side walls (319, 320) which areopposite each other. The frame (302 b) comprises two long side walls(328, 327) which are located opposite each other and two short sidewalls (321, 322) which are located opposite each other.

The preferred foil (303) comprises two layers (314, 315) with differentmelting points. One layer (311) has a lower melting point. This layer(311) is oriented towards the multiwell plate (301) with the heat rims(310, 311) and the surface (302 a) of the frame (302 b). During heatsealing, heat is transferred through the more stable layer (310) withthe higher melting point to layer (311) with the lower melting point.Layer (311) is, thus, heated and melted. The upper layer (310) is notmelted during heat sealing. This minimizes the risk of a leaking foil(303) (FIG. 45 (b)).

The multiwell plate (301) and lid (302) are assembled pairwise (300) forsupply. On the inside (316) of the top surface (317), the frame (302 b)comprises supporting ribs (318). Two supporting ribs (318) are locatedalong a first side wall (321) of the frame (302 b), and two supportingribs (318) are located along a second side wall (322) opposite of thefirst side wall (319). Preferably, said side walls are the short sidewalls of the frame (302 b). The edge of the top surface (313) of themultiwell plate (301) comprises openings (308). Said openings (308) arelocated along side walls (319, 320) corresponding to the side walls ofthe frame (321, 322) where the supporting ribs (318) are located. In theassembly/supply position of the lid (302) relative to the multiwellplate (301) (FIG. 44 (a)), the openings (308) are placed such that theydo not align with the supporting ribs (318). Thus, when the lid (302) isplaced on the multiwell plate (301), the supporting ribs (318) sit onthe top surface (313) of the multiwell plate (301) (FIG. 46 (a)). Thisprevents the foil (303) from contacting the heat rims (310, 311), and,thus, prevents scratches on the foil (303) that may otherwise be causedby slipping of one multiwell plate (300) over the surface of the foil ofa second multiwell plate (300) and which may impair the optical andmechanical properties of the foil (303) during transport, storage andloading.

When the microwell plate (301) with lid (302) is used in an analyticalinstrument (126), the lid (302) is lifted for addition of purifiedanalyte and reagents. When all reagents are added to the vessels (312),the lid (302) is rotated by 180° and placed on the multiwell plate (301)(FIGS. 44 (b) and (c)). The openings (308) on the top of the multiwellplate (301) and the supporting ribs (318) on the frame (302 b) arebrought into alignment by the 180° rotation. Thus, when placed on themultiwell plate (301), the foil (303) is brought into contact with theheat rims (311) surrounding the vessels (312) of the multiwell plate(301), and heat can be applied to seal the vessels (312) with the foil(303) (FIG. 44 d), FIG. 45 (a)).

Both microwell plate (301) and lid (302) comprise a length and width ofthe base corresponding to ANSI SBS footprint format. More preferably,the length is 127.76 mm +/−0.25 mm, and the width is 85.48 mm +/−0.25mm. They comprise openings (304) on plate (301) and openings (309) onlid (302) which are constructed and arranged to be gripped by a handler(500), either in pairwise arrangement or individually. Thus, it ispossible to grip and transport the assembled plate and frame (300), oronly the lid (302) or only the plate (301).

The multiwell plate (301) comprises a base (325) surrounding the bottomof the sidewalls (319 to 322) of the plate (301). Said base (325)comprises recesses (306). These recesses (306) can interact with apositioning and fixing element (124 a) on a holding station (330) of theanalyzer (126), as described hereinbefore for the Processing Plate. Theinteraction between the positioning and fixing element (124 a) and therecess (306) positions and fixes plate (301). This allows to keep theplate (301) fixed on the holding station (330) when handling the lid(302) independently of the plate (301). It also removes potentialtorsion or other types of unevenness of the plate (301). The fixing ofthe plate (301) also leads to a maximal contact surface between plate(301) and holding station (330). This equalizes potential differences instatic charge between holding station (330) and plate (301). Finally,the fixing also ensures that the vessels (312) all are located at thesame height, allowing for more precise pipetting.

The frame (302 b) comprises a recess (307). This recess is located atthe lower end of the side of the frame (302 b). The recess is preferablylocated in a different position than openings (304). Preferably, tworecesses (307) are located on one side of the frame (302), and tworecesses (307) are located on the opposite side of the frame (302 b).Most preferably, said recesses (307) are located in the same position asrecesses (306) on the multiwell plate (301). The recesses (307) ensurethat when the plate (301) is fixed by engagement of fixing elements (124a) and recesses (306) only the multiwell plate (301) is fixed, not thelid (302).

Analytical System with Hardware Coding of Consumables

An analytical system (440) comprising an automated analytical apparatus(400) for isolating and/or analyzing an analyte is disclosed. An“analyte” as used herein relates to any type of analyte of interest.Preferred analytes are polypeptides or nucleic acids. More preferably,the analyte is a nucleic acid. The analytical system (440) furthercomprises more than one type of consumables (60, 70, 101, 301, 302),wherein said consumables (60, 70, 101, 301, 302) have essentially a samefootprint, and wherein any type of consumables (60, 70, 101, 301, 302)comprises a unique surface geometry (601). Furthermore, the system alsocomprises a system comprising specific recognition elements fordistinguishing said different consumables wherein any one of saidrecognition elements comprises a unique surface geometry complementaryto a unique surface geometry of a specific type of consumable.Preferably, said system for distinguishing said different consumables(60, 70, 101, 301, 302) constructed and arranged to recognizespecifically said unique surface geometry (601).

The analytical system (440) disclosed herein is preferably a system(440) comprising a module (401) for isolating and/or purifying ananalyte. More preferably, the system (440) additionally comprises amodule (403) for analyzing said analyte to obtain a detectable signal.The detectable signal can be detected in the same module (401, 402,403), or, alternatively in a separate module. The term “module” as usedherein relates to any spatially defined location within the analyzer(400). Two modules (401, 403) can be separated by walls, or can be inopen relationship. Any one module (401, 402, 403) can be eitherautonomously controlled, or control of the module (401, 402, 403) can beshared with other modules. Preferably, all modules are controlledcentrally. Transfer between modules (401, 402, 403) can be manual, butis preferably automated. Thus, a number of different embodiments ofautomated analyzers (400) are encompassed by the present disclosure.

Consumables (60, 70) with essentially identical footprint are plasticconsumables for storing other consumables, such a pipette tips or singletubes, of for holding reagents and samples, or consumables (101, 301,302) holding reaction mixes in which the processing or analyzing of theanalyte are performed. Preferred embodiments of such consumables areracks (60, 70) or multiwell plates (101, 301, 302). Different types ofmultiwell plates (101, 301, 302) with identical footprint can preferablybe used in the system (440). Such preferred types of multiwell plates(101, 301, 302) are multiwell plates for storing samples or reagents,multiwell plates for isolating and analyzing an analyte, and/ormultiwell plates for reacting an analyte to obtain a detectable signal.In a preferred embodiment, if the analyte is a nucleic acid, thereacting may be any type of amplification of nucleic acids known to theperson skilled in the art. Preferably, said consumables (60, 70, 101,301, 302) comprise at least one tip rack (60, 70) and one multiwellplate (101, 301). Preferably, said footprint comprises a length andwidth of the base corresponding to ANSI SBS footprint format. Morepreferably, the length is 127.76 mm +/−0.25 mm, and the width is 85.48mm +/−0.25 mm.

The term “surface geometry” relates to the surface structure, preferablyof the side walls of the consumables (60, 70, 101, 301, 302). Thesurface geometry preferably comprises hardware identifiers (39, 7, 6,117, 118, 116, 102, 119, 115, 125, 305) more preferably recesses and/orridges integrally formed in the surface of a consumable (60, 70, 101,301, 302). Preferably, any one of all types of consumables (60, 70, 101,301, 302) with said footprint comprise a unique surface geometry (601).A “unique surface geometry” is understood to be a surface geometry (601)as hereinbefore described which is unique for a type of consumable (60,70, 101, 301, 302) and is substantially different from the surfacegeometries (601) of other consumables (60, 70, 101, 301, 302) such thatthe consumable (60, 70, 101, 301, 302) is specifically recognized by therecognition system (450) of the analytical system (440).

In a preferred embodiment, the system comprises stackers (600 a,b) forstacking multiple consumables (60, 70, 101, 301, 302) of one type,wherein any one of said stackers (600 a,b) comprises recognitionelements for one type of consumable (60, 70, 101, 301, 302). The term“stacker” as used herein relates to the uptake area in the analyticalsystem for a specific consumable (60, 70, 101, 301, 302). The multipleconsumables (60, 70, 101, 301, 302) of a specific type are stacked inthe stacker (600 a,b). Individual consumables (60, 70, 101, 301, 302) ofone type are then retrieved from the stacker (600 a,b) within the system(440) and automatically transported to the module (401, 402, 403) inwhich they are used, either by a conveyor or, preferably by a handler(500) connected to a robotic arm (502). Thus, due to the unique surfacegeometry (601) of the consumable (60, 70, 101, 301, 302), a specifictype of consumable (60, 70, 101, 301, 302) can only be loaded into aspecific stacker (600 a,b). This prevents the user from loading thewrong consumable (60, 70, 101, 301, 302) into a specific stacker (600a,b), even if the consumables (60, 70, 101, 301, 302) have the samefootprint.

In a preferred embodiment, more than two different types of consumables(60, 70, 101, 301, 302) with a same footprint are comprised in thesystem (440). In a more preferred embodiment, more than three differenttypes of consumables (60, 70, 101, 301, 302) with a same footprint arecomprised in the system (440). The consumables (60, 70, 101, 301, 302)are preferably selected from the group consisting of tip rack (60, 70),multiwell plate (101) for sample preparation, multiwell plate (302) foramplification and/or detection, reagent cassette holder, tube holderetc.

A method is also provided for recognizing the identity of a consumable(60, 70, 101,301,302) within an analyzer (400) as describedhereinbefore. Said method comprises providing one type of consumable(60, 70, 101, 301, 302), wherein said one type of consumable (60, 70,101, 301, 302) comprises a unique surface geometry (601). The methodfurther comprises interacting said one type of consumable (60, 70, 101,301, 302) comprising a unique surface geometry (601) with a stacker (600a,b) comprising recognition elements (602) specific for said uniquesurface geometry (601). The consumable (60, 70, 101, 301, 302) is thenidentified when the unique surface geometry (601) is engaged by therecognition elements (602). The term “recognition elements” as usedherein relates to elements, such as a guidance (602) mounted on theinside of a stacker (600 a,b) which fits specifically with the uniquesurface geometry (601) of one type of consumable (60, 70, 101, 301,302). Preferred analyzer (400), consumable (60, 70, 101, 301, 302) andstacker (600 a,b) are as defined hereinbefore.

Finally, a consumable (60, 70, 101, 301, 302) is also providedcomprising a unique surface geometry (601) constructed and arranged toallow a stacker (600 a,b) to specifically identify the type ofconsumable (60, 70, 101, 301, 302). Preferred embodiments of consumable(60, 70, 101, 301, 302), stacker (600 a,b) and surface geometry (601)are as hereinbefore described.

A schematic drawing of an exemplary analytical system (440) is shown inFIG. 51). The recognition of the surface geometry (601) by the stacker(600 a,b) is shown in FIG. 51. The inner surface of the stacker (600a,b) comprises recognition elements (602). It is constructed andarranged to engage the surface geometry (601) of the consumable (60, 70,101, 301, 302) and, thereby, the type of consumable (60, 70, 101, 301,302) is specifically recognized and loading of the wrong type ofconsumable (60, 70, 101, 301, 302) is avoided. In a preferredembodiment, more than one type of multiwell plate is used in theanalytical system (440), preferably in different steps of the analyticalmethod. Thus, different types of multiwell plates (101, 301, 302) havedifferent surface geometries that are unique for each type of multiwellplate (101, 301, 302). Each type of multiwell plate (101, 301, 302) isspecifically recognized by its unique surface geometry (601).

System with Spatial Separation

A new method and system with improved contamination prevention aredisclosed. In preferred embodiments, the contamination protection may befurther improved by combining the claimed method with any one of theknown contamination methods described above.

In one aspect of the method hereinbefore described, said first cellcomprises a first air pressure, and said second cell comprises a secondair pressure, wherein said first air pressure is higher than said secondair pressure.

In a preferred embodiment of the method, outside air which enters saidfirst cell is filtered. Filtering of air allows to reduce the risk ofcontaminants entering the analytical apparatus. Preferably, the filtersare HEPA filters.

Preferably, said first and second cell are separated by a wall.Separation of cells by walls further reduces the risk of potentialcontaminants from one cell entering another cell.

In one aspect of the present method, the purified analyte is transferredfrom said first cell to said second cell through an air-lock locatedbetween said first and second cell. Preferably, the air lock comprises adoor on the side of the first cell and a door on the side of the secondcell. In the resting state of the air lock, both doors are on the closedposition. The door on the side of the first cell opens when a plate hasto pass from the first cell to the second cell. The plate is then placedon a movable plate holder. Said plate holder is then moved into the airlock. The door on the side of the first cell closes. Then, the door onthe side of the second cell opens. The plate on the plate holder passesto the end of the air lock, and a handler then removes the plate fromthe plate holder of the air lock.

In a preferred embodiment of the method hereinbefore described, saidpurified analyte is comprised in a reaction vessel.

In one aspect of the present method, said reaction vessel is sealedprior to analyzing said analyte. Especially in the preferred field ofnucleic acid analytics, analyzing comprises multiplying the targetnucleic acid by amplification. Thus, during the analyzing process andfollowing analysis, the reaction vessels comprise large amounts of thetarget nucleic acid(s) which can be a potential source of contamination.Sealing of the reaction vessels, preferably with a foil, more preferablyby thermally sealing said reaction vessels with foil, further reducesthe risk of potential contamination of samples and purified nucleicacids prior to analysis. Preferably, the reaction vessel is sealed priorto transport from said first cell to said second cell. The contaminationprevention effect of sealing is, then, optimal.

In one aspect of the present method, a additional step comprisestransferring a sample from a sample vessel to a multiwell plate in athird cell, wherein said third cell has an air-flow which is separatefrom said first and second cell and wherein said step precedes the stepscarried out in the first cell. Preferably, the first cell is aprocessing cell as descried herein, the second cell is an analyticalcell as described herein and the third cell is a sample cell asdescribed herein.

In a preferred embodiment of the method, a first handler transfers saidreaction vessel from said first cell to said air-lock, and a secondhandler transfers said reaction vessel from said air-lock to said secondcell.

Preferred embodiments of cells are described hereinafter.

An automated analytical apparatus for processing an analyte is alsodisclosed, comprising:

a processing cell comprising a separation device for isolating andpurifying said analyte, wherein said processing cell has a first airflow;

an analytical cell for analyzing said analyte contained in a reactionvessel, wherein said analytical cell has a second air flow;

a transfer system for transferring a vessel comprising said purifiedanalyte from the processing cell to the analytical cell;

wherein said first air flow in said processing cell and said second airflow are separate.

In one aspect, said first cell comprises a first air pressure and saidsecond cell comprises a second air pressure, wherein said first airpressure is higher than said second air pressure. The advantages of saidaspect are as described hereinbefore.

In a preferred embodiment of the present method, an air-lock is locatedbetween said processing cell and said analytical cell. The advantages ofsaid embodiment are as described hereinbefore.

In one aspect of the present method, said automated analytical apparatusadditionally comprises a sample cell for transferring samples from asample vessel to a processing vessel.

In a preferred embodiment, said apparatus comprises separation wallslocated between said cells. The advantages of said embodiment are asdescribed hereinbefore.

Preferably, said sample cell comprises a filter for filtration of airflowing in said sample cell.

In one aspect of the apparatus, gaskets are comprised in the upperhousing of said processing cell.

In a preferred embodiment, said reaction vessel is capped or sealed.

In one aspect of the apparatus, said transfer system comprises a firsthandler for transferring said reaction vessel from said processing cellto said air-lock, and a second handler for transferring said reactionvessel from said air-lock to said analytical cell.

A preferred embodiments of the apparatus is a automated nucleic acidanalyzer comprising a process cell for sample preparation and anamplification cell.

Advantages and effects of said embodiments and aspects are as describedhereinbefore.

FIG. 54 shows a preferred embodiment of an apparatus. The apparatus(700) comprises a first cell (702), a second cell (703) and a third cell(701). Preferred embodiments of the cells are a sample cell (701) fordistributing samples to be analyzed, a process cell (702) for isolatingand purifying an analyte, and an amplification/detection cell (703) foramplifying and detecting a nucleic acid analyte. The sample cell (701)and process cell (702) comprise filters (730), preferably HEPA filters,for passing air into the apparatus. Sample cell (701) has an air-flow(741) and an air pressure (751), and process cell (742) has an air flow(742) and an air pressure (752), and amplification cell (703) has an airflow (743) and an air pressure (753). Preferably, the air pressures(751) and (752) are essentially identical. Air pressure (752) is higherthan air pressure (753), which prevents air from flowing fromamplification cell (703) to process cell (702). Walls (731) to (734) arelocated between the three cells (701) to (703). An air lock (710) islocated between process cell (702) and amplification cell (703).

FIG. 55 shows a side view (a) and a top view (b) of the air lock (710).The air lock (710) has a main body (723) and side walls (713) and a door(711) on the side of the process cell (702) and a second door (712) onthe side of the amplification cell (703). The doors (711), (712) aremovably attached to the main body by hinges (716). Inside the air lock(710), a movable carriage (714) is mounted. The carriage (714) comprisesa plate holder (720). On the carriage, at least one teach-bolt (721),preferably more than one teach-bolt (721) is mounted. The teach-bolt(721) serves as an orientation for the handler when the handler is inthe process of engaging the plate on the plate holder (720) or whenmoving the plate onto the plate holder (720). The carriage alsocomprises notches (721) which provide space for the gripper fingers ofthe gripper. The air-lock (710) also comprises gaskets (719) for properclosing of the closing of the doors (711), (712). The main body (723)further comprises, on each end, a mechanical stopper (718) for the doors(711) and (712). There is also a motor (715) attached to the main body(723) for moving the carriage (714).

FIG. 56 shows a preferred apparatus. The apparatus comprises, on thefront side, walls (761) and (762). The walls are movable to allow accessto the cells (701), (702) for the handler system (704). Preferably, thewalls (761, 762) are made of foil. They can be moved up and down. Theapparatus further comprises outer side walls (735).

Preferred embodiments of apparatuses, methods and systems are thosedescribed below which additionally comprise the features hereinbeforedescribed. Further preferred features of the apparatus are preferredembodiments described below.

Hardware Architecture

An analytical apparatus (400) for isolating and analyzing at least oneanalyte is also provided, comprising:

(i) at least one module (401) for receiving and dispensing a sample tobe analyzed,

(ii) at least one module (402) for isolating said analyte to beanalyzed,

(iii) at least one module (403) for analyzing said analyte,

wherein said modules (i) to (iii) are arranged along an axis. In apreferred embodiment, said modules are arranged along an X-axis. In asecond embodiment, said modules are arranged along a vertical axis. Saidmodules can also be arranged along an Y or a Z-axis. The axis may alsobe partly circular.

The apparatus further comprises at least one transport module (480) fortransferring consumables (60, 70, 101, 301, 302), wherein said at leastone transport module (480) is arranged parallel to said axis in front ofmodules (i) to (iii). The at least one transport module (480) preferablycomprises a handler (500) as described hereinafter. The apparatus (400)comprises at least one consumable holder (600), wherein said at leastone consumable holder (600) is arranged along said axis in front of saidmodules (i) to (iii). In a preferred embodiment, said consumable holder(600) is a stacker (600). Said stacker (600) preferably comprisesrecognition elements for recognizing consumables (60, 70, 101, 301,302). Preferably, said stacker (600) is arranged below said transportmodule (480).

The terms “analytical apparatus” (400) and “analyzer” (400) and“analytical instrument” (400) are used interchangeably.

Further preferred embodiments of said stacker (600) and analyticalapparatus (400) and analytical system (440) are described below.

The modules (401, 402, 403) of the analytical apparatus (400) arepreferably fixed to neighboring modules (401, 402, 403). In oneembodiment, the modules (401, 402, 403) are fixed to each other usingfixing elements, preferably screws. In another embodiment, the modules(401, 402, 403) are fixedly mounted in frames, and the frames ofneighboring modules are fixed to each other, preferably by fixingelements, more preferably by screws.

In one preferred embodiment of the apparatus hereinbefore described,said module (403) for analyzing said analyte comprises a thermal cycler.In a more preferred embodiment, the apparatus comprises at least twomodules (403) for analyzing said analyte, wherein said at least twomodules (403) for analyzing said analyte are mounted on two verticallevels. Other preferred embodiments of said module for analyzing saidanalyte comprise modules for detecting chemical reactions or modules fordetecting binding of antibodies to antigens. Further preferredembodiments of said module for analyzing said analyte are describedhereinafter.

The analytical apparatus (400) hereinbefore described, in a preferredembodiment, comprises more than two consumable holders (600).Preferably, at least one consumable holder is a consumable waste holder(650).

The analytical apparatus as described hereinbefore comprises, in apreferred embodiment, a module for preparing at least one reactionmixture for analyzing said at least one analyte, wherein said module isarranged between module (ii) and module (iii).

An analytical system (440) is also disclosed. An analytical system (440)comprises an analytical apparatus (400) as described herein. Ananalytical apparatus (400) comprises one or more modules or cells (401,402, 403). Said modules or cells comprise stations for carrying out theprocessing and/or analysis of an analyte. Preferably, said apparatus andsaid system are automated. More preferably, consumables are loadedmanually. An embodiment of the apparatus is shown schematically in FIG.52.

The arrangement of all modules of the apparatus facilitates loading ofconsumables into the apparatus by the user. The apparatus and theindividual modules are also more easily accessible for servicing thanexisting analytical apparatuses. The arrangement of the transport modulealong the same axis as the modules also allows an optimization of thefootprint of the entire apparatus and system because the transportmodule is used for loading of consumables into the apparatus as well asfor transfer of consumables between the different modules and the wasteholder.

An automated method for isolating and analyzing at least one analyte is,furthermore, disclosed, comprising the steps of

-   -   a) receiving a sample comprised in a sample container in a first        module for receiving and distributing samples,    -   b) transporting a first consumable from a consumable holder to        said first module for receiving and distributing samples with a        transport module,    -   c) distributing said sample into receptacles of a first        consumable for isolating an analyte comprised in said sample,    -   d) transporting said first consumable for isolating an analyte        comprised in said sample with said transport module from said        first module for receiving and dispensing samples to a second        module for isolating the analyte comprised in said sample,    -   e) isolating said analyte in said second module for isolating        the analyte,    -   f) analyzing said analyte in a third module for analyzing an        analyte.

The term “distributing” as used herein relates to the aspiration ofsample from a sample container, and subsequent dispensing intoreceptacles for holding a liquid. Preferred embodiments of saidcontainer are described hereinafter and hereinbefore, with reference tothe preferred embodiments of the analytical apparatus.

In a preferred embodiment of the method hereinbefore described, saidanalyte is transported by the transport module from said second modulefor isolating the analyte to said third module for analyzing an analyte.

In a further preferred embodiment of the automated method hereinbeforedescribed, the isolated analyte is transferred from said firstconsumable for isolating an analyte comprised in said sample to a secondconsumable for analyzing said analyte. Preferred embodiments of saidsecond consumable are described hereinafter.

The automated method further comprises a preferred embodiment whereinsaid second consumable for analyzing said analyte is transferred by thetransfer module from the second module for isolating the analyte to thethird module for analyzing an analyte.

More preferably, the transfer module comprises at least two transferdevices (500), wherein one transfer device transfers consumables fromthe consumable holder to module (i) or (ii), from module (i) to module(ii) and from module (ii) to an interface between module (ii) and module(iii), and from module (i), module (ii) or the interface to a wasteconsumable holder; and the second transfer device transfers consumablesbetween the interface and module (iii). Preferably, the transfer modulecomprises two transfer devices.

In a preferred embodiment, said method additionally comprises, betweensteps e) and f), the step of preparing reaction mixtures for analyzingsaid at least one analyte.

The flow of transported consumables is shown with arrows in FIGS. 52 (a)to (c).

Further preferred embodiments are described below.

Workflow Timing

A method and system of isolating and analyzing an analyte in anautomated analyzer are also disclosed, comprising the steps of providinga liquid sample comprising said analyte to a processing vessel in amodule of a first type; transferring said liquid sample comprising saidanalyte to a module of a second type; isolating and purifying saidanalyte in said processing vessel in said module of a second type;transferring said purified analyte to a module of a third type;analyzing said analyte in said module of a third type by reacting saidanalyte with reagents necessary to obtain a detectable signal. Thetiming for transfer and processing within any one module of one type ispre-defined, and said timing in any one module of one type is identicalfor any one analyte which is isolated and analyzed. Furthermore, thetiming of any one type of module can be independent of the timing of anyother type of module. Thus, the modules can work autonomously.

The advantage of the method and system is that the pre-defined timing ofany one module one type allows for optimization of the overall workflowtiming, and makes it possible to achieve an optimized high throughputfor analytical tests.

The pre-defined timing of the modules makes it possible to start theanalytical process, beginning with distribution of samples, only if, atthe end of the workflow of one module, a subsequent type of module forthe next step in the analytical process is available. Thus, for example,the isolation and purification of the analyte is only started if, at theend of the isolation and purification process, a module for analyzingthe isolated and purified analyte is available.

Thus, in a preferred embodiment, said analyzer comprises at least twomodules of a third type.

In a preferred embodiment of the method hereinbefore described an firstanalyte is isolated and analyzed in said automated analyzer, and asecond analyte isolated and analyzed in said automated analyzer, whereinsaid first and second analyte are isolated and analyzed in parallel,wherein said first analyte is analyzed in one of said modules of a thirdtype, and said second analyte is analyzed in a second one of saidmodules of a third type, and wherein the time for isolating andanalyzing said first and second analyte are identical.

Thus, the timing of the analytical tests run in parallel can be keptidentical such that any analyte is processed and analyzed in theanalytical apparatus under identical conditions. This also makes itpossible to use more than one module of one type in the automatedanalyzer while ensuring identical conditions for every test. Thepossibility to use multiple modules of one type makes it possible toadapt the throughput of the analytical apparatus to the needs of theuser.

In a preferred embodiment, said analyte is a nucleic acid analyte. Inother preferred embodiments, the analyte is an antibody, or an antigen,or a cell.

Preferably, said module of a third type is an amplification module.

In a preferred embodiment of the method hereinbefore described, saidautomated analyzer comprises at least two modules of a second type.

In a further preferred embodiment, said analyzer comprises at least fourmodules of a third type.

Preferably at least 48 samples comprising at least one analytes areisolated and purified in parallel. More preferably, said samples areisolated and purified in 96 well plates in parallel. Most preferably,the samples are analyzed in 96 well plates in at least one module of athird type.

In a preferred embodiment of the method hereinbefore described, at least192 samples comprising at least one analyte are isolated and purified inparallel in at least two separate modules of a second type, and areanalyzed in at least two separate modules of a third type. The time forprocessing within any one of the modules of a second type is identical,and the time for processing within any one of the modules of a thirdtype is identical. Thus, it is possible to isolate and purify analytesin 48 well plates in at least two modules of a second type in parallel,and to then analyse the purified samples in at least four modules of athird type.

Preferred embodiments for modules of a first type are sample cells fordistributing a sample comprising an analyte to a processing vessel.Sample cells and processing vessels are further described hereinafter.

Preferred embodiment for modules of a second type are cells forpurifying and isolating an analyte comprising a separation station. Suchcells are further described below.

Preferred embodiments of modules of a third type are analytical modules,more preferably cells for amplifying an analyte which is a targetnucleic acid. Preferred embodiments of such cells include temperaturecontrolled incubators, more preferably thermal cyclers.

Since the time required for analysis of a sample in a module of a thirdtype, preferably an amplification and detection module, is longer,preferably twice as long as the isolation and purification of a samplecarried out in a module of a second type, a maximum throughput can beobtained by using a setup as shown in FIG. 53 c) by using twice theamount of modules of a third type than modules of a second type.

The preferred workflow of any one module is described by the followingmethod steps:

-   -   Loading of all required consumables via pre-defined interfaces;    -   Loading of samples via pre-defined interfaces;    -   Initiation of a test when all samples to be analysed and all        required consumables are loaded;    -   Output of the result in the form of treated samples (e.g.        isolated and purified samples) or of measured data or monitoring        results;    -   Output or disposal of used materials;    -   Output or disposal of analyzed samples.

More preferably, said workflow additionally comprises, for the module ofa second type, the loading of reagents.

The transferring in the transfer system is manual or automated.Preferably, the transfer is automated. The transfer system transfersconsumables and certain reagents between modules and storage areas.Preferred embodiments of storage areas are described below. A furtherpreferred storage area is a fridge.

The apparatus used in the method hereinbefore described preferablycomprises a linear transfer module. In another embodiment, it preferablycomprises a rotational transfer module.

The timing of the transfer system which connects the modules is notcritical. This means that manual operations on the system during theprocess, such as loading with consumables, or loading of samples intoany one of the modules, do not affect the workflow of the overallsystem. Also, pauses between two types of modules are, thus, possiblewithout affecting the workflow in the critical processes (those inmodules of a first type, of a second type and of a third type).

Preferably, in the method hereinbefore described, the time for isolatingand purifying and analyzing any one analyte is identical to the time forisolating and purifying and analyzing any other analyte.

In a preferred embodiment, the process of providing and isolating andpurifying at least one analyte is started conditional on theavailability of a module of a third type when the process of isolatingand purifying and preparing of reaction mixtures is terminated.

The method disclosed herein also makes it possible to generate systemscomprising multiple analytical apparatuses with said modules, or toconnect multiple systems while ensuring that the critical workflowsremain constant and that any one analyte is isolated, purified andprocessed in the system under identical conditions. This improvesprecision, accuracy and reliability of the analytical tests performed inparallel. It is also possible, with the claimed method, to introducepauses that are not critical for the analytical test when the process ina module of one type is finished, and before the workflow of thesubsequent type of module is started. However, such pauses are notpossible for time-critical steps.

The method and system hereinbefore described may additionally alsocomprise a module of a fourth type for preparing reactions for analysisin the module of a third type; and a module of a fifth type fordetecting a reaction performed in said module of a third type.Preferably, analysis of an analyte comprises both reaction and detectionin said module of a third type.

Further preferred embodiments of the method hereinbefore described aredescribed herein.

While the foregoing invention has been described in some detail forpurposes of clarity and understanding, it will be clear to one skilledin the art from a reading of this disclosure that various changes inform and detail can be made without departing from the true scope of theinvention. For example, all the techniques and apparatus described abovecan be used in various combinations. All publications, patents, patentapplications, and/or other documents cited in this application areincorporated by reference in their entirety for all purposes to the sameextent as if each individual publication, patent, patent application,and/or other document were individually indicated to be incorporated byreference for all purposes.

1. A method for isolating and analyzing an analyte that may be presentin a fluid sample, the method comprising the automated steps of a)transferring said fluid sample from a sample vessel to a processingvessel with a pipette tip of a first type; b) combining together a solidsupport material and said fluid sample in a well of said processingvessel for a period of time and under conditions sufficient to permitsaid analyte to be immobilized on the solid support material; c)isolating the solid support material from other material present in thefluid sample in a separation station; and d) purifying the analyte inthe separation station by separating the fluid sample from the solidsupport material and washing the materials one or more times with a washbuffer; wherein said pipette tip of a first type used in step a) isre-used after step a), and wherein said pipette tip of a first type isstored in a rack comprising pipette tips of a first type and pipettetips of a second type.
 2. The method of claim 1, wherein step a)comprises: a1) engaging pipette tips of a first type which are held in arack in a first position with a first process head; a2) transferringsaid fluid sample from a sample vessel to a processing vessel withpipette tips of a first type engaged to a first process head; a3)placing said pipette tips in said rack and disengaging said pipette tipsfrom said process head; a4) transporting said rack comprising saidpipette tips and said processing vessel to second positions; and a5)engaging said pipette tips of a first type which are held in said rackwith a second process head in said second position.
 3. The method ofclaim 1, wherein said analyte is a nucleic acid.
 4. The method of claim1, wherein said transporting of said rack comprising said pipette tipsand said processing vessel to a second position occurs between aseparate first cell of an analytical instrument and a separate secondcell of said analytical system.
 5. The method of claim 1, wherein saidrack comprises independent chambers to accommodate pipette tips.
 6. Themethod of claim 1, wherein said first type of pipette tips is re-usedfor the washing in step d).
 7. An analytical system for processing ananalyte, said system comprising: a) a first position comprising a firstreceptacle holding a liquid sample comprising an analyte, a secondreceptacle for holding a liquid sample, a rack holding pipette tips, anda first process head for transferring a liquid sample from the firstreceptacle to a second receptacle; b) a second position comprising astation for receiving said second receptacle, and a rack holding stationfor receiving said rack; and c) a transfer system for transferring thesecond receptacle and the rack holding pipette tips between the firstposition and the second position.
 8. The analytical system of claim 7,wherein the positions are separate cells.
 9. The analytical system ofclaim 7, wherein the rack transferred by said transfer system comprisespipette tips which were used in the first position.
 10. The analyticalsystem according to claim 7, wherein the first receptacle is a samplevessel and the second receptacle is a processing vessel.
 11. Theanalytical system according to claim 7, wherein said processing vesselis a multiwell vessel.
 12. The analytical system according to claim 7,wherein the transport system transfers the receptacle and the rack fromthe first position to the second separate position.
 13. The analyticalsystem of claim 7, wherein said transport system comprises a handlerconstructed and arranged to grip and transport said rack and saidprocessing vessel from a first to a second location within the system.14. An automated analyzer for detecting an analyte comprising a) aplurality of stations disposed within said analyzer, wherein theplurality of stations comprises: i) a sample dispensing station disposedin a first location, said sample dispensing station being constructedand arranged to dispense liquid sample comprising an analyte from asample vessel to a processing vessel with pipette tips held in a rack;ii) a separation station disposed in a second location, wherein saidseparation station is constructed and arranged to receive saidprocessing vessel holding said liquid sample and said rack holdingpipette tips used in the sample dispensing station and to separate ananalyte from other material present in the liquid sample; and iii) areaction station disposed in a third location, wherein said reactionstation comprises a temperature-controlled incubator for incubating saidanalyte with reagents necessary to obtain a detectable signal; b) atransport mechanism constructed and arranged to transport said samplevessel and said rack from said sample dispensing station to saidseparation station.